Research Progress on Tumor-Associated Macrophages and PD-1/PD-L1 Inhibitors in Advanced Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related mortality worldwide. Currently, surgical resection remains the cornerstone of curative treatment for CRC; however, patients with advanced disease continue to face significant risks of postoperative recurrence and metastasis. Although immune checkpoint inhibitors (ICIs), represented by PD-1/PD-L1 monoclonal antibodies, have reshaped the therapeutic landscape of various solid tumors, their clinical benefit in CRC is strictly limited by mismatch repair (MMR) status, leaving the vast majority of proficient mismatch repair/microsatellite stable (pMMR/MSS) patients with minimal therapeutic gain. Importantly, tumor-associated macrophages (TAMs)—a key regulatory component of the tumor immune microenvironment—not only exert immunosuppressive functions through PD-1 and multiple other pathways, but also promote PD-1 expression on tumor cells via distinct mechanisms. Consequently, accumulating evidence suggests that TAMs play a critical role in mediating resistance to PD-1/PD-L1 inhibitors in CRC. Nevertheless, research on the underlying mechanisms remains at an early stage. This narrative review aims to summarize the latest advances regarding the involvement of TAMs in resistance to PD-1/PD-L1 blockade, with a particular focus on strategies to enhance immunotherapy responsiveness through TAM modulation. We further discuss limitations in current clinical studies and propose potential directions for future research. By juxtaposing successful mechanistic studies with underwhelming clinical trial data, we aim to redefine the therapeutic rationale for combining TAM-targeted agents with immune checkpoint blockade.

Plain Language Summary

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, and its treatment outcomes are strongly influenced by the tumor immune microenvironment (TIME). Macrophages are immune cells that act as the body’s “cleaners” and “regulators”, but within tumors, they are often “recruited” to support cancer growth and spread. These cells are known as tumor-associated macrophages (TAMs). This review summarizes key recent studies on TAMs in colorectal cancer, including findings from both experimental and clinical research. Evidence shows that TAMs contribute to tumor growth, angiogenesis, and immune evasion, and may also affect the response to immunotherapies such as PD-1/PD-L1 inhibitors. Various intervention strategies are under investigation, including targeting TAM metabolism, signaling pathways (such as STAT3 and CXCR4), or polarization states (M1/M2 types) to suppress tumor progression. Moreover, the application of single-cell sequencing has revealed the remarkable diversity of TAM populations, providing new opportunities for more precise regulation of their functions. In the future, macrophage-centered immunotherapy strategies may offer more effective treatment options for patients with colorectal cancer and other malignancies.

Keywords

colorectal neoplasms immune checkpoint inhibitors immune checkpoint proteins macrophages tumor microenvironment

1. Background

Colorectal cancer (CRC) ranks among the most prevalent malignancies globally. According to the World Health Organization, CRC is the third most commonly diagnosed cancer—accounting for approximately 10% of all cancer cases—and stands as the second leading cause of cancer-related mortality worldwide. While the widespread implementation of effective screening measures has led to a decline in CRC incidence and mortality rates, there has been a concerning trend toward a younger age at onset in recent years. Although surgery is generally recommended for patients at all stages of CRC, the rate of postoperative recurrence in patients with middle-to-advanced stage disease remains a significant concern. Data indicates that the 5-year risk of postoperative recurrence in patients with advanced disease is 35.5%, a figure that can be reduced to 26.9% with the administration of neoadjuvant chemotherapy.¹ Consequently, it is imperative to investigate novel therapeutic strategies aimed at downstaging tumors preoperatively to improve surgical resectability, reducing postoperative recurrence, and minimizing adverse effects.

Immunotherapy, particularly immune checkpoint inhibitors (ICIs)—administered either as monotherapy or in combination regimens—has demonstrated potent antitumor activity across a spectrum of solid tumors, including gastrointestinal malignancies. Clinically, preoperative immunotherapy has been shown to increase the rate of R0 resections and decrease the likelihood of postoperative recurrence. However, in the context of CRC, robust responses to classical PD-1/PD-L1 inhibitors (accompanied by fewer side effects) are largely limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) status. In contrast, patients with proficient mismatch repair/microsatellite stable (pMMR-MSI-L) tumors—who constitute the vast majority of the CRC population—typically fail to respond to these therapies. Therefore, elucidating the mechanisms underlying resistance to PD-1/PD-L1 inhibitors and developing innovative therapeutic strategies are critical priorities.

Tumor-associated macrophages (TAMs) constitute a critical component of the tumor immune microenvironment (TME). As the most abundant infiltrating immune cells within the TME, they are recruited by various factors and polarized into two primary phenotypes: M1 and M2. In tumor tissues, infiltrating TAMs are predominantly of the M2 phenotype, playing a pivotal role in tumorigenesis and progression through their pro-tumorigenic activities. Through interactions with various cell types within the tumor tissue, M2-TAMs mediate immune escape as well as invasive and metastatic phenotypes. Previous studies have established that TAM polarization exhibits high plasticity, allowing for dynamic interconversion in response to changes within the TME. In contrast to M2-TAMs, M1 macrophages can potentiate the anti-tumor immune response of other immune cells within the TME, thereby enhancing tumor cell sensitivity to therapeutic agents. Consequently, modulating the infiltration levels and functional phenotypes of TAMs in tumor tissue may enhance patient responsiveness to immunotherapy, ultimately improving clinical prognosis. Existing literature underscores the significant research value of TAMs as potential targets for CRC immunotherapy. In this narrative review, we summarize research from recent years regarding TAMs in CRC and explore the rationale, challenges, and potential of combining macrophage-modulating agents with PD-1/PD-L1 inhibitors. This narrative review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines.²

A comprehensive literature search was conducted using the PubMed, Web of Science, and Embase databases to identify relevant studies published up to January 2026. The search strategy utilized combinations of the following keywords: “colorectal cancer”, “tumor-associated macrophages (TAMs)”, “PD-1/PD-L1 inhibitors”, “immunotherapy resistance”, “macrophage polarization”, and “tumor microenvironment”. We specifically targeted articles discussing the mechanistic crosstalk between TAMs and the PD-1/PD-L1 axis, as well as preclinical and clinical studies involving TAM-modulating agents (including CSF-1R, CCR2, and CD47 inhibitors). The selection criteria prioritized high-quality primary studies, clinical trials, and systematic reviews published in English, with a particular focus on recent advancements occurring within the last five years to ensure the timeliness of the evidence.

2. PD-1/PD-L1 Inhibitors

2.1. Mechanisms of Immunotherapy

Programmed cell death protein 1 (PD-1), encoded by the PDCD1 gene, is a type I transmembrane protein composed of 288 amino acids. It is expressed on the surface of various immune cells and is particularly upregulated on tumor-specific T cells.^3,4 The ligand for PD-1, PD-L1, is expressed across diverse tumor cell types and triggers an inhibitory signaling pathway upon binding to PD-1.⁵ Following the interaction with PD-L1, the immunoreceptor tyrosine-based inhibitory motif (ITIM) and the immunoreceptor tyrosine-based switch motif (ITSM) within the cytoplasmic tail of PD-1 undergo phosphorylation. This phosphorylation event recruits SH2 domain-containing phosphatase 2 (SHP2), thereby initiating T cell inactivation.⁶ Consequently, key signaling molecules within the T cell receptor (TCR) and the CD28 co-stimulatory pathways are dephosphorylated and attenuated. This cascade suppresses the cytotoxic function of cytotoxic T lymphocytes (CTLs) and ultimately induces the apoptosis of activated T cells.⁷

As of 2025, the U.S. Food and Drug Administration (FDA) has approved multiple PD-1/PD-L1 inhibitors for the treatment of dozens of distinct cancer types, encompassing a broad spectrum from common malignancies to rare tumors.⁸ By blocking the PD-1/PD-L1 axis, these inhibitors restore the cytotoxic capacity of activated T cells against tumor cells, thereby exerting an anti-tumor effect. Furthermore, in the context of gastric cancer, multiple studies have demonstrated that patients receiving combination chemotherapy and neoadjuvant PD-1 inhibitors exhibit activation of autophagy. Sun et al. proposed that neoadjuvant chemoimmunotherapy not only directly downregulates PD-L1 via the p62/SQSTM1-NF-κB pathway but also suppresses PD-L1 expression by reducing histone deacetylase (HDAC) levels, thus contributing to the activation of tumor immunity.⁹ Building on the substantial success of clinical trials, ten anti-PD-1 antibodies (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various cancer indications.⁵ While PD-1/PD-L1 inhibitors have been integrated into the NCCN and ESMO guidelines for malignancies such as non-small cell lung cancer (NSCLC), metastatic melanoma, and renal cell carcinoma, their application in colorectal cancer remains an area of active investigation.

Current understanding of the mechanisms underlying resistance to PD-1/PD-L1 inhibitors remains incomplete; however, it is widely accepted that heterogeneity in the type, abundance, function, and spatial distribution of immune cells within the tumor microenvironment (TME) contributes significantly to therapeutic resistance. Notably, the PD-1/PD-L1 axis is not the sole determinant of anti-tumor immune suppression. Various cytokines, such as IL-10, TGF-β, IL-4, and IL-13, also play a role.¹⁰ Additionally, diverse cellular components, including tumor-associated macrophages (TAMs) and fibroblasts, participate in establishing an immunosuppressive phenotype.¹¹ Therefore, for malignancies that exhibit a suboptimal response to PD-1/PD-L1 inhibitor monotherapy, the combined application of other immunomodulatory agents may enhance anti-tumor efficacy through synergistic mechanisms, thereby significantly improving the objective response rate (ORR) and survival benefits for patients. Such combination strategies hold significant potential for overcoming primary resistance and remodeling the tumor microenvironment.

2.2. Challenges in CRC

While PD-1/PD-L1 inhibitors have demonstrated significant therapeutic efficacy in patients with colorectal cancer (CRC), this benefit is largely confined to a small subset of patients; the majority fail to exhibit a substantial response.¹² The mismatch repair (MMR) status of CRC patients appears to be a critical biomarker determining responsiveness to immune checkpoint inhibitors (ICIs). Based on mutational profiles, CRC can be stratified into two distinct groups: tumors characterized by deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) status with a high overall tumor mutation burden (TMB), and those with proficient mismatch repair/microsatellite stable (pMMR/MSI-L) status, which exhibit a significantly lower mutational load.¹³ Clinical investigations, exemplified by the NICHE trial, have revealed a striking disparity in efficacy between dMMR and pMMR cohorts following neoadjuvant combination therapy with nivolumab and ipilimumab.¹⁴ The pathological response within the dMMR cohort was remarkable, with nearly all patients achieving a major pathological response (MPR) and a high rate of pathological complete response (pCR). Conversely, while the overall response rate in the pMMR cohort was significantly lower, an MPR was nonetheless observed in a subset of patients.¹⁴ Similarly, the NEST-1 trial (NCT05571293) and the study on preoperative targeted therapy for molecularly selected resectable colorectal cancer (UNICORN; NCT05845450) have demonstrated therapeutic activity for neoadjuvant regimens within pMMR cohorts. These findings suggest that immunosuppression in pMMR CRC is not irreversible; rather, there remains a potential window for immune responsiveness achievable by modulating tumor burden, altering the composition of the microenvironment, and optimizing the timing of immune activation. Furthermore, accumulating evidence indicates that immunosuppression and metabolic dysregulation mediated by tumor-associated macrophages (TAMs) may constitute the primary barriers contributing to the insensitivity of pMMR CRC to ICIs. Consequently, building upon these neoadjuvant studies, therapeutic strategies that target TAMs or remodel the immune network represent a rational approach to enhancing the responsiveness of pMMR CRC to immunotherapy.

Mechanistically, studies have shown that TMB is significantly elevated in dMMR/MSI-H CRC compared to pMMR/MSI-L CRC. This increased TMB in dMMR/MSI-H tumors results in a mutation rate up to 20-fold higher than that of pMMR/MSI-L tumors, driving a more robust anti-tumor immune response. This is reflected in significant differences in the composition and function of immune infiltration within the tumor immune microenvironment (TIME).¹⁵ Loupakis et al. suggested that higher TMB and increased abundance of tumor-infiltrating lymphocytes (TILs) in patients with dMMR/MSI-H CRC are associated with a superior response to immune checkpoint inhibitor therapy.¹⁶ Liu et al. discovered that in dMMR tumors, M2c-like TAMs are depleted via S100A6/P53-induced apoptosis, resulting in enhanced immune activity, a more favorable prognosis, and increased sensitivity to immunotherapy. Conversely, in pMMR tumors, M2c-like TAMs persistently differentiate into a pro-tumorigenic phenotype; their high infiltration rates contribute to an immunosuppressive microenvironment, correlating with poorer prognosis and diminished therapeutic response.¹⁷ Concurrently, research indicates that patients with pMMR CRC can be stratified to determine potential benefit from immunotherapy through assessments such as absolute T-cell counts, Immunoscore, TMB analysis, or PD-L1 expression levels.¹⁸ Furthermore, a multitude of novel immunotherapeutic strategies targeting diverse molecular checkpoints are currently under active development.

3. TAMs

3.1. Introduction to TAMs

The tumor immune microenvironment (TME)—often analogized as the “soil” of the tumor—is a dynamic and intricate regulatory system that plays a pivotal role in tumor progression and metastasis.¹⁹ Composed of tumor cells, tumor-associated macrophages (TAMs), lymphocytes, fibroblasts, vasculature, and the extracellular matrix, the TME exerts a profound influence on the biological characteristics of the tumor.²⁰ Among these components, TAMs represent the most abundant infiltrating immune cell population within the TME.²¹ TAMs originate primarily from circulating monocytes, which are recruited to distinct tumor regions by a variety of tumor-secreted growth factors and chemokines—such as CSF-1, CCL2, VEGF, and TGF-β—where they subsequently differentiate into distinct subtypes, including classically activated M1 macrophages and alternatively activated M2 macrophages.²² In colorectal cancer (CRC), M2-like TAMs, which drive tumor progression, predominate in both abundance and function within the TME; notably, the overexpression of M2 markers, such as CD163, is positively correlated with poor prognosis, chemotherapy resistance, and metastatic risk.²³ Through interactions with lymphocytes, B cells, NK cells, and tumor cells via cytokines, chemokines, and other mediators, TAMs facilitate tumor cell proliferation, invasion, metastasis, and drug resistance, thereby regulating the direction and intensity of the immune response through diverse mechanisms.²⁴ Furthermore, metabolic crosstalk is ubiquitous within the TME, where metabolites circulate among cells. As messengers of intercellular communication, specific TME-derived metabolites are engulfed by TAMs, altering their phenotype and function; conversely, TAMs modulate the TME via metabolic reprogramming to foster tumor progression.²⁵ For instance, lactate produced by the enhanced glycolytic activity of cancer cells leads to TME acidification, which stimulates M2 polarization and upregulates HMGB1 in TAMs; this, in turn, elevates HMGB1 levels in CRC cells, thereby promoting their migratory behavior.²⁶

TAM polarization toward the M2 phenotype promotes CRC immune evasion and tumor progression primarily by suppressing CD8+ T cells. TAMs express PD-1/PD-L1, a pathway critical for tumor immune escape. Blockade of the PD-1/PD-L1 signaling pathway has been shown to reduce the proportions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and TAMs within the TME, thereby enhancing T-cell cytotoxic activity and inhibiting CRC growth.²¹ Additionally, exosomes, non-coding RNAs, and cytokines derived from multiple sources shape the immunosuppressive microenvironment by modulating TAM polarization, protein expression, and cytokine release to inhibit CD8+ T cells. Beyond interactions with CD8+ T cells, the maintenance of an immunosuppressive state involves crosstalk between TAMs and various other cell types. For example, the binding of the Sirpα receptor on myeloid cells to CD47 on tumor cells triggers a signal that blocks myeloid phagocytosis, effectively facilitating tumor immune evasion.²⁷ In CRC liver metastases, a macrophage-fibroblast network has been identified that promotes an immunosuppressive TME.¹¹ These findings suggest that immunotherapies targeting TAMs could disrupt the immunosuppressive microenvironment of CRC, offering a novel therapeutic strategy when combined with conventional chemotherapy or immunotherapy.

The recruitment of TAMs by CRC-derived cytokines and their subsequent polarization into M2 macrophages constitute critical mechanisms promoting tumor metastasis, particularly via the CCL2/CCR2 and CSF-1/CSF-1R axes.^28,29 TAMs modulate the invasive properties of CRC cells by producing pro-inflammatory IL-6, a cytokine capable of activating the JAK2/STAT3 pathway to promote invasion.³⁰ Furthermore, various exosomes and extracellular vesicles facilitate the interaction between CRC cells and TAMs by carrying non-coding RNAs; these cargoes activate pathways such as RhoA/ROCK, PI3K/AKT, and JAK2/STAT3, thereby promoting the metastatic phenotype of CRC cells and establishing a reciprocal feed-forward loop with M2 macrophage polarization.

Angiogenesis is recognized as a hallmark phenotype of malignancy, and anti-angiogenic therapies have been implemented across various cancer types.³¹ In the TME, TAMs promote angiogenesis by directly secreting VEGF; the resulting neovasculature exhibits hyperpermeability, which has been confirmed to be associated with drug-resistant phenotypes in CRC.³² TAMs are extensively involved in every step of the angiogenic process: they facilitate the degradation of the basement membrane by producing matrix metalloproteinases (MMPs) and cathepsins, and they secrete pro-angiogenic growth factors—such as VEGF, PDGF, basic FGF (bFGF), and the chemokines CCL2 and CXCL8—which provide the vascular network necessary not only for maintaining cancer cell growth but also for facilitating dissemination.³³

3.2. TAM Polarization

Plasticity and functional polarization are hallmarks of the mononuclear phagocyte system.³⁴ In response to diverse signals within the tumor microenvironment (TME), circulating monocytes differentiate into tumor-associated macrophages (TAMs), exhibiting distinct gene expression profiles and functional states driven by specific environmental cues. Current classification paradigms categorize macrophages into classically activated M1 and alternatively activated M2 phenotypes, with the latter further subdivided into M2a, M2b, M2c, and M2d subtypes. M1 macrophages secrete pro-inflammatory cytokines (including TNF-α, IL-6, IL-1, IL-12, ROS, CXCL9, CXCL10, CXCL11, CCL2, CCL3, CCL4, and CCL5) and potentiate inflammatory responses, thereby exerting anti-cancer effects by enhancing intratumoral immunity.²⁴ Conversely, M2 macrophages, characterized by specific surface markers and the secretion of factors such as VEGF, TGF-β, EGF, IL-10, and PD-L1, facilitate tissue repair and angiogenesis; however, they are widely recognized for their role in suppressing anti-tumor immunity and promoting tumor progression and metastasis.³⁵

Cytokines serve as pivotal drivers of macrophage differentiation. Undifferentiated macrophages (M0), when stimulated by pro-inflammatory factors such as IFN-γ, LPS, TNF-α, and GM-CSF, undergo M1 polarization via the activation of transcription factors including STAT1, NF-κB (p65), and IRF5; this state is defined by the upregulation of markers such as IL-6, IL-12, and iNOS.³⁶ In contrast, stimulation with IL-4, IL-10, IL-13, or M-CSF activates STAT6, PPARγ, and IRF4, driving M2 polarization and upregulating markers such as Arg-1, CD206, and STAT6.³⁷

Non-coding RNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are increasingly recognized as critical regulators of the epithelial-mesenchymal transition (EMT) and TME dynamics during tumor progression.^38,39 Exosomes mediate intercellular communication by transporting these bioactive cargos—including lncRNAs, miRNAs, circular RNAs (circRNAs), and proteins—which play crucial roles in the crosstalk between tumor and stromal cells.²⁵ For instance, CRC-derived exosomes have been shown to promote disease progression by delivering lncRNAs that facilitate M2 macrophage polarization.⁴⁰

Furthermore, metabolic dysregulation involving glucose and lipid metabolism significantly influences TAM polarization. Obesity, a recognized risk factor for CRC, frequently induces alterations in lipid metabolism. In this context, TAMs exhibit upregulated uptake of long-chain polyunsaturated fatty acids, leading to intracellular lipid accumulation and elevated fatty acid oxidation (FAO). Increased FAO activity stimulates mitochondrial oxidative phosphorylation and reactive oxygen species (ROS) production, which ultimately suppresses NF-κB activation and pro-inflammatory cytokine production via the activation of the STAT6 pathway.⁴¹ Regarding glucose metabolism, while normal cells primarily rely on mitochondrial oxidative phosphorylation, most solid tumors depend on aerobic glycolysis (the Warburg effect). This metabolic shift results in the accumulation of substantial lactate, leading to acidification of the TME. Lactate accumulation has been shown to promote the extracellular secretion of HMGB1 by macrophages, thereby enhancing cancer cell growth and metastasis.²⁶ Moreover, lactate-mediated lactylation of RIG-I at lysine 852 inhibits NF-κB activation and drives M2 macrophage polarization, representing a critical mechanism by which the tumor-resident microbiota promotes CRC liver metastasis.⁴²

Notably, M1 and M2 phenotypes are not static; rather, TAMs retain the capacity to dynamically interconvert in response to evolving conditions within the TME. Therefore, exploring the molecular mechanisms governing TAM polarization not only deepens our understanding of CRC pathogenesis but also provides valuable insights for the development of innovative therapeutic strategies.²⁸

3.3. Prognostic Significance of TAMs in CRC

The role of TAMs in the prognosis of colorectal cancer (CRC) is characterized by its complexity and multifaceted nature. Conventionally, M2-polarized TAMs have been associated with poor clinical outcomes due to their well-documented roles in promoting angiogenesis, immunosuppression, and tumor metastasis.⁴³ However, recent investigations have revealed that this relationship is not absolute within the context of CRC. For instance, a study by Brambilla et al. demonstrated that although M2-like TAMs (CD163+, CD206+) are ubiquitous in CRC tissues, their density does not exhibit a statistically significant correlation with patient survival; indeed, in certain contexts, high TAM infiltration may paradoxically correlate with favorable clinical outcomes.⁴⁴ The study further observed superior survival rates in patients harboring metalloproteinase mutations, suggesting that the prognostic value of TAMs may be modulated by the molecular background of the tumor.⁴⁴ Furthermore, research indicates that the prognostic impact of TAM infiltration is heavily dependent on spatial distribution. Yang et al. reported that the infiltration density of M2-TAMs at the invasive front of the tumor is significantly higher than that in the tumor center.⁴⁵ Crucially, this study confirmed that the CD163+/CD68+ ratio at the invasive front serves as an independent predictor of poor recurrence-free survival (RFS) and overall survival (OS) in CRC patients, offering superior predictive accuracy compared to traditional total TAM enumeration.⁴⁵ These findings imply that TAM function is dictated not only by polarization status but also by interactions with other components of the tumor microenvironment. Consequently, the binary M1/M2 classification may be insufficient, and defining more granular subtypes could be essential for elucidating the complex roles of TAMs across various malignancies.

Accumulating evidence suggests that relying solely on TAM density or polarization status to predict CRC prognosis has inherent limitations. Conversely, a combined assessment of TAMs and tumor-infiltrating lymphocytes (TILs)—particularly CD8+ T cells—yields more reliable prognostic information. For example, Majid et al. noted that high TAM infiltration is associated with favorable survival only when accompanied by a high density of CD8+ T cells; in the absence of sufficient T-cell infiltration, high TAM density conversely indicates a poor prognosis.⁴⁶ This observation suggests the existence of functional crosstalk between TAMs and T cells within the TME, which collectively shapes the immune response landscape and subsequently influences disease progression and therapeutic response. Therefore, the synergistic impact of TAMs and T cells on CRC prognosis provides a more integrated perspective for understanding the colorectal cancer immune microenvironment and lays the groundwork for future therapeutic strategies aimed at modulating TAMs to bolster anti-tumor immunity.

3.4. TAMs and PD-1/PD-L1

In colorectal cancer (CRC), a bidirectional regulatory crosstalk exists between TAMs and the PD-1/PD-L1 immune checkpoint pathway, which collectively shapes the immunosuppressive tumor microenvironment. Multiple spatial omics and single-cell studies have identified myeloid cells (including TAMs and monocyte-derived macrophages) as a primary source of PD-L1 (CD274) expression within the CRC microenvironment. Notably, these cells are spatially colocalized with exhausted or functionally suppressed T-cell populations, suggesting that they likely participate in the inhibition of anti-tumor T-cell responses via the PD-1/PD-L1 axis.^47,48 Mechanistically, tumor- and stroma-derived signals can drive TAM polarization toward an immunosuppressive phenotype and induce PD-L1 upregulation. For instance, IFN-γ-mediated JAK/STAT signaling, as well as various inflammation- and metabolism-related pathways, can enhance PD-L1 expression in myeloid cells, thereby impairing CD8+ T-cell proliferation, cytotoxicity, and cytokine secretion.⁴⁹ Conversely, M2-polarized TAMs secrete cytokines such as IL-10, TGF-β, and CCL5, which activate STAT3 and NF-κB signaling pathways in both tumor cells and TAMs themselves; this results in the significant upregulation of PD-L1 expression, further exacerbating T-cell exhaustion mediated by the PD-1/PD-L1 axis.^50-52 It is also noteworthy that PD-1 expression is not exclusive to T cells; specific subsets of tumor-associated myeloid cells and macrophages also express PD-1, and signaling through this receptor in the tumor environment has been shown to restrict their phagocytic capacity and anti-tumor function.⁵³

From a therapeutic perspective, CRC—particularly the microsatellite stable (MSS) or pMMR subtypes—demonstrates limited overall response to PD-1/PD-L1 inhibitor monotherapy. Consequently, accumulating evidence supports strategies that target or reprogram the TAM/myeloid suppressive network to potentiate immune checkpoint blockade (ICB) efficacy. These strategies include inhibiting myeloid recruitment or immunosuppressive pathways, as well as modulating TAM phenotypes, thereby improving T-cell infiltration and function to enhance ICB response.^13,54 Thus, the TAM-PD-1/PD-L1 axis constitutes not only a pivotal component of immune evasion in CRC but also a critical entry point for developing combination therapies for MSS/pMMR CRC.

3.5. TAMs and Resistance Phenotypes in CRC

While direct evidence establishing a positive correlation between high infiltration of typical M2-TAMs and resistance to PD-1/PD-L1 inhibitors in CRC is currently limited, multiple basic and translational studies suggest that TAM phenotypes are intrinsically linked to sensitivity to immune checkpoint inhibitors (ICIs). For instance, in dMMR/MSI-H CRC, M2c-like TAMs are depleted via S100A6/p53-mediated apoptosis, leading to enhanced immune activity and increased sensitivity to ICIs.¹⁷ Furthermore, PD-1 blockade has been shown to restore phagocytic function in PD-1-high TAMs across various tumor models, suggesting that specific TAM subsets retain a degree of sensitivity to PD-1/PD-L1 inhibitors.⁵³ Conversely, persistent high infiltration of immunosuppressive M2-TAMs is generally associated with a “cold tumor” phenotype and suboptimal therapeutic efficacy of ICIs.^49,55,56

Accumulating evidence indicates that M2-TAMs directly drive both primary and acquired resistance to PD-1/PD-L1 inhibitors in CRC by suppressing CD8+ T cells through multiple pathways, including the PD-1/PD-L1 axis. On one hand, M2-TAMs overexpress inhibitory molecules such as PD-L1 and B7-H4 within the tumor microenvironment. Through the PD-1/PD-L1 axis and other co-inhibitory pathways, they induce CD8+ T-cell exhaustion, rendering these T cells unable to fully recover proliferation and cytotoxic activity even following PD-1/PD-L1 blockade.^49,56 On the other hand, M2-TAMs upregulate metabolic enzymes such as ARG1, IDO, and CD39/CD73, which deplete arginine and tryptophan while accumulating immunosuppressive metabolites like adenosine. This forces CD8+ T cells into a state of “metabolic exhaustion” due to energy and nutrient deprivation, preventing the complete restoration of effector function despite PD-1/PD-L1 signaling blockade.⁵⁷ Furthermore, M2-TAMs facilitate immune evasion in CRC by secreting immunosuppressive cytokines, such as IL-10 and TGF-β, which inhibit T-lymphocyte activity.⁴⁹ Concurrently, the competitive consumption of nutrients like glucose by TAMs and tumor cells, coupled with the accumulation of metabolites such as lactate, further restricts T-cell glycolysis and mitochondrial function, thereby diminishing their immune response capacity.⁵⁷ Consequently, M2-TAMs synergistically impair CD8+ T cells through a triple mechanism: “structural” (high PD-L1 expression), “functional” (secretion of immunosuppressive factors), and “metabolic” (nutrient competition and metabolic reprogramming) (Figure 1). This multifaceted suppression serves as a fundamental basis for the limited efficacy of PD-1/PD-L1 monotherapy and the development of resistant phenotypes in pMMR/MSS CRC, providing a solid theoretical rationale for combining TAM modulators to overcome resistance to immune checkpoint inhibitors.

Figure 1.

Schematic diagram illustrating the multidimensional mechanisms of M2 TAM-mediated resistance to PD-1/PD-L1 blockade in colorectal cancer. In the CRC microenvironment, M2 TAMs suppress CD8+ T-cell function via three distinct mechanisms, thereby driving resistance to immunotherapy: Structural inhibition: Driven by JAK/STAT signaling, M2 TAMs upregulate PD-L1 expression to directly engage PD-1 on T cells, effectively abrogating cytotoxic signaling. Functional inhibition: TAMs secrete immunosuppressive cytokines (e.g., IL-10, TGF-β) that not only directly inhibit T-cell activity but also potentiate STAT3/NF-κB survival pathways within tumor cells. Metabolic inhibition: By depleting essential nutrients (glucose, tryptophan, and arginine) and accumulating metabolites (lactate and adenosine), TAMs establish a metabolic barrier hostile to T-cell survival. Collectively, these mechanisms induce effector T-cell exhaustion and ultimately lead to the clinical failure of immune checkpoint inhibitors

4. TAMs, PD-1/PD-L1, and Immunotherapy in CRC

4.1. TAM Modulators in CRC

Given the pivotal roles of TAMs in CRC based on their distinct polarization states, significant strides have been made in exploring TAM-modulating agents for CRC therapy in recent years. Currently, therapeutic strategies targeting TAMs in CRC can be categorized into four primary approaches: reprogramming TAMs, depleting TAMs, modulating TAM recruitment, and regulating TAM metabolism.

4.1.1. Reprogramming TAM Polarization

TAM polarization is governed by a multitude of signaling pathways, with current research predominantly focusing on STAT3, STAT6, the STING pathway, and Toll-like receptor (TLR) pathways. Toll-like receptors (TLRs), serving as core pattern recognition receptors of the innate immune system, play intricate roles in regulating the differentiation, polarization, and function of TAMs.⁵⁸ Leveraging this mechanism, Wang et al. developed a triple-combination therapy comprising HMGN1, R848, and an anti-TNFR2 antibody.⁵⁹ In this regimen, the TLR4 agonist HMGN1 and the TLR7/8 agonist R848 activate myeloid cells within the tumor microenvironment (TME), while the anti-TNFR2 antibody suppresses regulatory T cells (Tregs). This strategy promotes a Th1-type immune response and concurrently resolves the immunosuppressive state induced by Tregs and M2-like macrophages. In a CRC mouse model, this triple therapy achieved a cure rate of 80% and established long-term tumor-specific immunity in the cured mice.⁵⁹

4.1.2. Depleting TAMs

Given that M2-like TAMs predominate in both abundance and function within the CRC TME, it has been postulated that the elimination of TAMs could ameliorate the anti-tumor immune state. Strategies include blocking the CSF-1/CSF-1R signaling pathway (e.g., using the inhibitor BLZ-945) or employing bisphosphonates to directly deplete TAMs.⁶⁰ However, anti-CSF-1R therapy alone may fail to completely eradicate pro-tumorigenic TAM subsets, resulting in limited therapeutic efficacy.²¹ Furthermore, the prognostic value of TAMs in CRC remains a subject of debate; some studies suggest that CD68+ TAMs at the invasive front may correlate with improved survival, and indiscriminate depletion could inadvertently impair T-cell function.⁶¹

4.1.3. Modulating TAM Recruitment

TAMs originate primarily from circulating monocytes that are recruited to specific tumor regions by a variety of tumor-secreted growth factors and chemokines (e.g., CSF-1, CCL2, VEGF, and TGF-β), where they subsequently differentiate into distinct subtypes.²² Consequently, blocking recruitment pathways represents a major strategy for TAM modulation. Among these, the CCL2-CCR2 axis is the most extensively studied and critical pathway. CRC tumor cells and stromal cells continuously secrete C-C motif chemokine ligand 2 (CCL2), which binds to C-C motif chemokine receptor 2 (CCR2) on circulating monocytes, triggering their directional migration, infiltration, and differentiation into TAMs.⁶² Therefore, blocking the CCL2-CCR2 axis—primarily through CCR2 antagonists (e.g., Carlumab, Maraviroc) or anti-CCL2 neutralizing antibodies—serves as a direct strategy to abrogate TAM recruitment. Similar to CSF-1R inhibitors, agents targeting the CCL2-CCR2 axis have encountered challenges in clinical translation. As monotherapy, they have demonstrated limited objective response rates. For instance, the CCR2 inhibitor Maraviroc showed limited clinical efficacy in trials.⁶³

4.1.4. Regulating TAM Metabolism

Metabolic profiles differ significantly between distinct TAM polarization states, and these metabolic pathways ultimately dictate TAM function in anti-tumor immunity. Notably, the regulation of glucose metabolism exerts a profound impact on TAM function. Aerobic glycolysis and oxidative phosphorylation (OXPHOS) are two critical metabolic pathways influencing TAM biology, although the underlying mechanisms are complex and context-dependent for both M1 and M2 phenotypes.⁶⁴ Therefore, selectively modulating the glucose metabolism of macrophages represents a potential avenue for malignancy treatment. AMPK, acting as a cellular energy “sensor,” remodels the energy metabolic patterns of macrophages by regulating metabolic pathways, thereby influencing their polarization direction (M1 vs. M2) and functional phenotype. Upon activation, AMPK directly inhibits mTORC1 activity and blocks downstream HIF-1α (hypoxia-inducible factor-1α) signaling, thereby suppressing aerobic glycolysis in TAMs.^65,66 For example, metformin can inhibit oxidative phosphorylation by targeting mitochondrial complex I; this alteration in cellular energy status activates AMPK, which subsequently potentiates NF-κB signaling, inhibits HIF-1α and mTOR/AKT signaling, promotes the expression of M1-associated cytokines (e.g., IL-12, TNF-α), and suppresses M2-associated factors.^67,68 This effect has been validated in both CRC and osteosarcoma models through in vitro and in vivo experiments.^68,69

4.2. TAMs and CRC Immunotherapy

As previously discussed, a primary limitation of PD-1/PD-L1 inhibitors in the treatment of colorectal cancer (CRC) lies in the recalcitrance of patients with pMMR tumors—who constitute the vast majority of CRC cases—to these therapies. Mechanistically, in mismatch repair-deficient (dMMR) CRC, TAMs with an anti-tumor phenotype undergo increased apoptosis, resulting in enhanced tumor immunity, improved prognosis, and greater sensitivity to immunotherapy. Conversely, within mismatch repair-proficient (pMMR) tumors, anti-tumor TAMs persistently differentiate toward a pro-tumorigenic phenotype; their high infiltration rate remodels the immunosuppressive microenvironment, thereby significantly compromising patient prognosis and therapeutic response.¹⁷ Based on these observations, we posit that TAMs serve not only as critical biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors but also as promising therapeutic targets whose modulation could directly improve clinical outcomes in CRC patients.

Despite significant progress in preclinical research regarding TAM modulators in CRC, most TAM-targeting strategies have yet to demonstrate definitive clinical benefits in trials, largely due to the complexity of the tumor microenvironment. Notably, the spatial distribution of TAMs in CRC tissues exhibits significant heterogeneity: M2-like TAMs are specifically enriched at the invasive front, a feature directly correlated with pro-tumorigenic invasion and metastasis, whereas the tumor center typically displays a mixed M1/M2 phenotype, though M2 dominance persists.⁶⁰ This spatial heterogeneity may be a key mechanism explaining why current TAM modulators often achieve only disease stabilization rather than complete remission.⁷⁰ Furthermore, recent studies suggest that the prognostic value of TAMs in CRC is strictly T-cell dependent: high TAM infiltration density correlates with favorable survival only when accompanied by high CD8+ T-cell density; conversely, in the presence of insufficient T-cell infiltration, elevated TAM density serves as an indicator of poor prognosis.⁴⁶ Therefore, we contend that only by simultaneously modulating TAM polarization and relieving the suppression of CD8+ T cells can anti-tumor immunity be significantly enhanced to achieve optimal therapeutic efficacy.

Building upon the mechanistic interplay between TAMs and T cells within the CRC immune microenvironment, we propose that combination therapy involving TAM modulators and PD-1/PD-L1 inhibitors represents a transformative strategy. By blocking TAM-mediated immunosuppressive pathways and concurrently releasing T-cell checkpoint inhibition (thereby activating CD8+ T-cell cytotoxic function), this synergistic approach has the potential to achieve a fundamental remodeling of the immune state in pMMR CRC, offering a promising solution to overcome the resistance challenges associated with monotherapy.

4.3. Combination Strategies of TAM Modulation and PD-1/PD-L1 Blockade

4.3.1. Enhancing TAM Phagocytosis

Phagocytosis represents a primary mechanism through which macrophages execute their immune functions. Phagocytic clearance mediated by myeloid cells, including macrophages, is tightly governed by cell surface receptors. The cluster of differentiation 47 (CD47) protein, expressed on both healthy and malignant cells, transmits a “don’t eat me” signal upon binding to the signal regulatory protein α (SIRPα) receptor on myeloid cells, playing a pivotal role in maintaining this equilibrium.⁷¹ Given that the CD47-SIRPα interaction limits anti-cancer immune responses, therapies inhibiting CD47 signaling hold the potential to promote macrophage-mediated phagocytosis of tumor cells, thereby restraining tumor growth. However, owing to the ubiquitous expression of CD47, the use of anti-CD47 antibodies poses safety concerns, particularly off-target effects such as anemia.⁷² Bispecific antibodies (BsAbs) have emerged as a safer and more effective alternative, enabling precise targeting of tumor cells while simultaneously blocking two distinct checkpoints. For instance, Yang et al. engineered PPAB001, a BsAb targeting both CD47 and CD24 for breast cancer treatment; animal studies demonstrated that this antibody upregulates TAM phagocytosis while promoting M1 polarization and CD8+ T-cell infiltration, without inducing side effects such as anemia.⁷² Similarly, Shao et al. designed a peptide-based bispecific antibody (pBsAb) by conjugating a monoclonal antibody with an EGFR-binding cyclic peptide. This agent bridges EGFR-overexpressing cancer cells and SIRPα-expressing macrophages, initiating macrophage-cancer cell interaction and enhancing EGFR-targeted antibody-dependent cellular phagocytosis (ADCP).⁷³ Furthermore, Jin et al. identified a small molecule compound, SMC18, which effectively blocks both PD-1/PD-L1 and CD47/SIRPα interactions in cell and animal models. Unlike monoclonal antibodies, small molecule drugs lack an Fc region, thereby avoiding antibody-dependent cellular cytotoxicity (ADCC) side effects while synergistically inhibiting tumor growth by enhancing TAM phagocytosis and relieving CD8+ T-cell immunosuppression.⁷⁴

In the field of CRC, preliminary clinical data regarding the CD47-SIRPα pathway have recently emerged. An open-label, single-arm study (NCT05167409) evaluated the CD47 blocker evorpacept (ALX148) in combination with pembrolizumab and cetuximab in patients with refractory microsatellite stable metastatic colorectal cancer (MSS mCRC).⁷⁵ Cetuximab was included to promote ADCP via antibody opsonization. Among 16 evaluable patients, the objective response rate (ORR) was 6.3%, the disease control rate (DCR) was 12.5%, with a median progression-free survival (mPFS) of 2.3 months and median overall survival (mOS) of 10.9 months.⁷⁵ These results suggest that even within the context of a typical immune “cold tumor,” this combination strategy exhibits limited anti-tumor activity. Notably, the study reported two drug-related fatalities (diagnosed as hemophagocytic lymphohistiocytosis [HLH] and cytokine release syndrome [CRS], respectively), leading to the cessation of enrollment.⁷⁵ This safety signal indicates that superimposing “phagocytosis checkpoint blockade” (CD47 inhibition) upon “T-cell checkpoint blockade” (PD-1 inhibition), alongside antibodies that enhance inflammatory or effector functions, may trigger severe systemic immune-inflammatory risks, posing a tangible challenge for clinical development.

Consequently, existing evidence supports positioning CD47-targeted therapy as a direction requiring “refined optimization.” Future research should focus on: developing molecular formats with higher tumor selectivity to mitigate off-target risks due to broad target expression; balancing efficacy and toxicity through dose exploration and optimized sequencing; and stratifying patients based on tumor burden, baseline inflammatory status, tumor CD47/PD-L1 expression levels, and myeloid phagocytosis-related biomarkers. These measures aim to maximize therapeutic benefit while minimizing the risk of severe adverse events such as CRS and HLH.

4.3.2. Depleting Inhibitory TAMs

Within tumor tissues, chemokines and cytokines produced by tumor and stromal cells—such as cancer-associated fibroblasts (CAFs)—induce the migration of peripheral blood monocytes into the tissue and their differentiation into TAMs.⁷⁶ Cytokines secreted by CAFs, including CSF-1, CCL2, and CXCL14, collectively promote the recruitment and polarization of monocyte-macrophages. CSF-1 acts as the primary driver of this process, regulating macrophage survival, differentiation, and tissue homeostasis through binding to the CSF-1 receptor (CSF-1R).^77,78 Intriguingly, CSF-1R exerts a dual role in CRC: in the absence of ligand binding, CSF-1R triggers apoptosis, inhibiting cancer development; upon ligand binding, however, it induces an epithelial-mesenchymal transition (EMT) phenotype in CRC cells and triggers lung metastasis.⁷⁹ In CRC tissues, CSF-1R expression is silenced in tumor cells due to enhancer methylation but is highly expressed in TAMs due to hypomethylation, identifying TAMs as the primary source of CSF-1R.⁷⁹ Thus, CRC cells evade apoptotic mechanisms due to receptor deficiency, while an abundance of ligand binds to CSF-1R on TAMs, inducing M2 differentiation and maintaining their survival. Consequently, CSF-1R is considered a highly potent therapeutic target.

Preclinical studies have demonstrated that treatment with the CSF-1R inhibitor PLX3397 (Pexidartinib) depletes TAMs in tumors, as evidenced in mouse models of breast cancer and malignant peripheral nerve sheath tumors.^80,81 However, its role in CRC remains less defined. Shimizu et al. showed that due to the lack of CSF-1R in CRC cells, Pexidartinib monotherapy did not significantly inhibit tumor growth in mice; however, it successfully reversed the immunosuppressive state of the TME. Crucially, when combined with anti-PD-1 therapy, it exhibited significant tumor suppression.⁸² This indirectly suggests that the inefficacy of anti-PD-1/PD-L1 therapy in microsatellite unstable CRC may stem from a paucity of anti-tumor immune cells within the TME.

These preclinical findings have been further tested and extended in preliminary clinical explorations. The Phase I MEDIPLEX study (NCT02777710) evaluated pexidartinib combined with durvalumab (anti-PD-L1 mAb) in patients with advanced/metastatic CRC or pancreatic ductal adenocarcinoma.⁶¹ Results showed limited objective response (only rare partial responses and some disease stabilization), leading to early termination. However, mechanistic analysis revealed instructive immunological changes: elevated peripheral CSF-1 levels and alterations in monocyte subsets confirmed effective inhibition of the CSF-1R pathway; conversely, a decline in peripheral dendritic cell (DC) subsets and impaired function were also detected.⁶¹ This phenomenon may be attributed to pexidartinib’s inhibition of FLT3 and c-KIT in addition to CSF-1R, potentially interfering with DC differentiation and maturation. Thus, while the drug achieved “myeloid de-repression,” it likely compromised antigen presentation, thereby offsetting the immune activation effects of PD-L1 blockade. The authors suggested that employing antibodies with higher specificity for CSF-1R might represent a more effective strategy.⁶¹

4.3.3. TAM Reprogramming

As previously discussed, TAM polarization in malignancies often exhibits a strong bias toward the M2 phenotype, while the polarization, function, and distribution of M1-TAMs are frequently suppressed. Therefore, converting pro-tumorigenic M2-TAMs into anti-tumor M1-TAMs, or altering functional states (e.g., enhancing phagocytosis, inhibiting angiogenesis) to reverse immunosuppressive properties, represents a viable therapeutic strategy.⁶⁰ The mechanism and validity of this approach have been verified in various malignancies.⁸³ However, some scholars caution that exogenous intervention in TAM polarization could disrupt immune homeostasis.⁶⁰ Thus, continuous research into the origin, function, and interactions of TAMs within the TME is critical for developing precise and effective therapies. These advances hold promise not only for improving CRC prognosis but also for addressing other cancers with similarly complex microenvironments.

Histone deacetylases (HDACs) are overexpressed in multiple cancer types, including CRC, breast cancer, and lung cancer. HDACs are key epigenetic enzymes that regulate gene deacetylation and expression, thereby modulating cancer cell apoptosis, growth, senescence, differentiation, immunogenicity, and tumor angiogenesis.⁸⁴ Consequently, various HDAC inhibitors (HDACis), such as vorinostat and romidepsin, have been investigated for cancer therapy and approved by the FDA for refractory cutaneous and peripheral T-cell lymphomas.^85,86 Han et al. demonstrated the value of the class IIa HDAC inhibitor TMP195 in CRC treatment. In colitis-associated cancer (CAC) and subcutaneous xenograft mouse models, TMP195 reduced tumor burden and increased the proportion of M1 macrophages; while lacking direct cytotoxicity as a monotherapy, it significantly inhibited tumor growth when combined with anti-PD-1 therapy.⁸⁷

However, current clinical studies generally indicate that efficacy remains limited in MSS/pMMR CRC. For instance, the Phase II CAROSELL study (NCT03993626) of CXD101 (HDACi) plus nivolumab observed partial responses and a high immunological disease control rate (iDCR), suggesting relief of immunosuppression in some patients. In contrast, another combination of an HDAC inhibitor and PD-L1 antibody showed no objective responses in a CRC cohort (NCT03812796), indicating that “HDAC+ICI” is not a universally effective sensitization strategy.^88,89 Notably, the recent randomized Phase II CAPability-01 study (NCT04724239) further suggested that in MSS/pMMR mCRC, doublet therapy with the PD-1 inhibitor sintilimab and the HDAC inhibitor chidamide yielded an ORR of 0%; however, the addition of the anti-VEGF agent bevacizumab increased the ORR to 15.2% and improved survival outcomes. This implies that synchronous intervention against vascular/stromal barriers and myeloid immunosuppression may be required to translate “epigenetic remodeling + ICI” into stable clinical benefits.⁹⁰

4.3.4. Inhibiting TAM Recruitment

The CXCL12/CXCR4 axis constitutes a critical chemokine pathway recruiting monocytes to the tumor microenvironment. CXCL12, secreted by tumor cells or stromal cells (such as cancer-associated fibroblasts), binds to its receptor CXCR4, directly attracting CXCR4-expressing monocytes to infiltrate tumor tissues and differentiate into TAMs.⁹¹ Particularly in hypoxic tumor regions, CXCR4 expression on macrophages is significantly upregulated, further enhancing TAM migration and retention in these niches.⁹² Consequently, inhibitors of the CXCL12/CXCR4 pathway have demonstrated therapeutic potential in oncology, inflammatory diseases, and stem cell mobilization. Plerixafor (AMD3100), already used clinically for various malignancies, has been confirmed to inhibit the progression of cancers such as lymphoma and prostate cancer.⁹³ Research by Biasci et al. (NCT02179970) indicated that in MSS pancreatic and colorectal cancers, Plerixafor blocks the CXCL12/CXCR4 axis to alleviate the immunosuppressive TME. When combined with PD-1/PD-L1 inhibitors, it synergistically enhances the anti-tumor immune response, significantly inducing T-cell infiltration, tertiary lymphoid structure formation, and multidimensional immune activation (INTIRE).⁹⁴ In this study, PET-CT results from two CRC patients (in the 40 μg/kg/h cohort) showed significant metabolic changes (≥30% increase in weighted mean SUV), suggesting potential immune activation, although data on ORR and overall survival (OS) have not yet been reported.

A representative clinical study targeting the CXCL12/CXCR4 axis is OPERA (KEYNOTE-559, NCT03168139), which employed the CXCL12 inhibitor NOX-A12 (olaptesed pegol) combined with pembrolizumab in a cohort including 11 CRC and 9 pancreatic cancer patients.⁹⁵ Results showed that while no partial or complete responses (PR/CR) by RECIST criteria were observed, 25% of patients achieved stable disease (SD) (approximately 27% in the CRC subgroup). The median PFS was approximately 1.87 months, with 6-month and 12-month OS rates of approximately 39% and 20%, respectively; notably, about 15% of patients survived beyond one year.⁹⁵ Furthermore, sequential biopsies revealed ubiquitous CXCL12 enrichment within tumors, and changes in CXCL12 levels post-treatment correlated with Th1-like tissue responses and disease stability. Concurrently, clues of immune activation, such as altered T-cell clustering/spatial distribution and upregulation of chemokine profiles (e.g., CXCL9/10), were evident.⁹⁵ These findings suggest that the core function of inhibiting this pathway likely lies in relieving immunosuppression and facilitating immune cell infiltration, thereby ameliorating the TME to create favorable conditions for subsequent immunotherapy or combination regimens. Therefore, future R&D strategies should prioritize screening likely beneficiaries (e.g., patients with high CXCL12 expression or immune-excluded phenotypes) and exploring rational combination schemes—such as integration with chemotherapy, anti-angiogenic agents, or radiotherapy—to synergistically promote antigen release and immune cell recruitment, ultimately improving clinical response rates. All the studies discussed in this section are summarized in Table 1 and Table 2.

Table 1.

Characteristics of Representative Research

Author	Country	Year	Animal	n	Groups	Tumor model	Intervention strategy	Outcome measures
Jin et al.⁷⁴	China	2024	mice	15	3	MC38	SMC18	tumor volume
Shao et al.⁷³	China	2024	NA	NA	NA	HT29	pBsAbs	antibody-dependent cellular phagocytosis (ADCP) activity
Han et al.⁸⁷	China	2022	mice	NA	2	CAC	TMP195	tumor volume, tumor weight

Table 2.

Characteristics of the Representative Clinical Studies

Study	Country	Year	Enrollment	MSI/MMR	Intervention strategy	Primary outcome measures	Research status	Results
NCT05167409	United States	2022	48	MSS	ALX148	RD ORR	Active, not recruiting	YES
NCT02777710	France	2019	47	MSI-H/MSI-L/MSS	Pexidartinib	ORR DLT	Active, not recruiting	NO
NCT03993626	United Kingdom	2018	55	MSS	CXD101	iDCR	Unknown	NO
NCT03812796	United Kingdom	2019	75	pMMR	4SC-202	DLT ORR	Unknown	NO
NCT04724239	China	2021	48	MSS/pMMR	chidamide	PFS	Unknown	NO
NCT02179970	United Kingdom	2019	26	MSS	Plerixafor	IMP	Active, not recruiting	NO
NCT03168139	Germany	2017	20	-	NOX-A12	Pharmacodynamics Safety - adverse events	completed	NO

5. Conclusion and Future Directions

The analysis presented in this review suggests that targeted modulation of TAMs represents a rational strategy for reversing resistance to PD-1/PD-L1 blockade in CRC patients. However, despite the abundance of research investigating TAM modulators in CRC, the therapeutic efficacy of combining TAM modulators with PD-1/PD-L1 inhibitors in clinical trials remains limited. Previous studies have delineated a broad spectrum of TAM modulation strategies, including the inhibition of TAM recruitment and polarization, metabolic regulation (involving glucose, lipid, and amino acid metabolism), and the induction of M1-like polarization. Furthermore, various signaling pathways governing TAM polarization and immunosuppressive phenotypes—such as STAT3, STAT6, Toll-like receptors (TLRs), and the STING pathway—possess significant potential as therapeutic targets.

Current therapeutic strategies for TAM modulation face several limitations. Key challenges include establishing a refined TAM subtyping system to identify specific therapeutic targets; elucidating the core molecular mechanisms by which TAMs mediate resistance to PD-1/PD-L1 blockade; and optimizing strategies to balance the maintenance of M1-TAM function with the selective inhibition of M2-TAMs within the TME. Moreover, systematic research evidence regarding pharmacoeconomic evaluation, precise definition of indications, and toxicity profile management for combination regimens of TAM modulators and PD-1/PD-L1 inhibitors remains insufficient.

Notwithstanding these challenges, the combination of macrophage modulators and PD-1/PD-L1 inhibitors remains a promising therapeutic strategy. TAM modulators hold the potential to transform the landscape of immunotherapy for various malignancies, including CRC, and preclinical evidence clearly underscores the necessity of testing these approaches in clinical settings. Future exploration of strategies, particularly those centered on macrophage modulation, holds the potential to expand and potentiate therapeutic efficacy, establishing TAM modulators as viable treatment options for cancer patients in the clinical setting. Furthermore, elucidating TAM diversity at the single-cell level and understanding macrophage ontogeny may provide novel perspectives for advancing cancer treatment and offer valuable insights for the clinical translation of macrophage-targeted immunotherapeutic strategies.

Footnotes

Acknowledgements

The authors utilized the AI language model Gemini to improve the readability and language quality of this manuscript.

ORCID iD

Shihao Ning

Consent to Participate

This article does not contain any studies with human participants performed by any of the authors.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by “Key Research and Development (R&D) Projects of Shanxi Province” (2021XM22) and “Fundamental Research Program of Shanxi Province” (202103021224346) and Shanxi Province “136 Revitalization Medical Project Construction Funds” (2019XY005).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data availability is not applicable to this article as no new data were created or analyzed in this study.*

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