Sage Journals: Discover world-class research

Abstract

Immune checkpoint regulation is a negative feedback regulatory mechanism in the body, and sequential death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) are known as immune checkpoints. The PD-1/PD-L1 pathway inhibits the activity of effector T cells through a negative regulatory mechanism to avoid excessive response-induced body damage. PD-L1 is highly expressed in many tumor tissues, and high PD-L1 expression can ultimately lead to tumor immune escape. Therefore, immune checkpoint blockade with inhibition of negative immune regulation therapy has become a cutting-edge hot spot for antitumor therapy, with the main target molecules being PD-1 and PD-L1. Recent years have seen promising progress in the study of traditional Chinese medicines and their effects on gastric and colon cancers, particularly in relation to the PD-1/PD-L1 pathway mechanisms. This review specifically examines the modulation of the PD-L1 pathway by certain traditional Chinese medicines in gastric and colon cancers, aiming to provide insights for the development of innovative drugs for these types of digestive cancers.

Keywords

traditional Chinese medicine PD-1/PD-L1 gastric cancer colon cancer

Immune checkpoint regulation is a negative feedback mechanism in the body that regulates the immune response through ligand–receptor binding.¹ Programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) are known as immune checkpoints.² PD-L1 is widely expressed in T cells, B cells, monocytes, and macrophages, as well as in a variety of tumor cells.^3,4 PD-1 coupled with PD-L1 on the cell surface inhibits the proliferation of T lymphocytes and the release of interleukin (IL) and other immunostimulatory factors from T cells.⁵ PD-L1 can also block B-cell activation.^6,7 The PD-1/PD-L1 pathway inhibits the activity of effector T cells through the negative regulatory mechanism described above, thereby preventing excessive response-induced damage to the organism.⁸

Tumor immune escape is the phenomenon in which tumor cells evade recognition and attack by the immune system.^9,10 PD-L1 is highly expressed in many tumor tissues.¹¹ The high expression of PD-L1 can eventually lead to tumor immune escape.^2,12 Therefore, blocking the binding of PD-1 to PD-L1 can reverse the above-mentioned immunosuppressive mechanism and help improve the ability of the body's immune system to kill tumors.¹³ Immune checkpoint blockade therapy, which suppresses negative immune regulation, has become a topic of interest in the field of antitumor therapy.¹³ The most well-known target is PD-1/PD-L1.^9,14

There has been encouraging progress in immune checkpoint inhibition research targeting gastrointestinal tumors. A series of immune checkpoint inhibitors, represented by PD-1/PD-L1 inhibitors, have been approved for use in a variety of gastrointestinal cancers, including gastric cancer and colon cancer. To date, FDA-approved PD-L1 inhibitors such as pembrolumab and nabumab have entered the market. Gastric cancer is an important contributor to cancer deaths globally and is now the second leading cause of cancer deaths worldwide.¹⁵ Clinical studies have shown that upregulation of PD-L1 in gastric cancer patients often predicts a poor prognosis.^16-19 PD-L1 is even a tumor-associated fibroblast (TAF) stimulator that directly stimulates the growth of gastric cancer cells.²⁰ It is effective and safe for treating advanced gastric cancer, suggesting that immune checkpoint inhibitors acting on PD-L1 may be an important tool for future treatment of gastric cancer. Colon cancer is a common malignant tumor worldwide, with the third and second highest incidence in men and women, respectively.^21,22 Nivolumab (another FDA-approved PD-L1 inhibitor) can be combined with pembrolizumab. The phase II clinical trial CheckMate142 for dMMR/MSI-H colorectal cancer (CRC) showed favorable clinical outcomes.²³ Regarding combination therapy with nivolumab, a manageable safety profile, high disease control rates, and significant survival benefit have been demonstrated.

Despite the effectiveness of PD-1/PD-L1 immune checkpoint inhibitors in treating tumors, challenges such as drug resistance and adverse effects persist. Drug resistance notably diminishes the efficacy of anti-PD-1/PD-L1 immunotherapy. Moreover, while PD-1/PD-L1 immune checkpoint inhibitors can bolster the immune system's defenses against cancer, they also trigger immune-related adverse reactions. Excessive immune system activation may harm normal body tissues, highlighting the significance of adverse reactions associated with PD-1/PD-L1 immune checkpoint inhibitors.²⁴ Hence, there is an urgent need for research on novel PD-1/PD-L1 immune checkpoint inhibitors.

In recent years, research on the effects of traditional Chinese medicine in treating gastric and colon cancers and its PD-1/PD-L1 pathway mechanism has also made positive progress. This review focuses on the PD-L1 mechanism of gastric cancer and rectal colon cancer, 2 common cancers of the digestive system, as well as the modulation of the PD-1/PD-L1 pathway by some traditional Chinese medicines, with the aim of opening up new ideas for the development of novel digestive system cancer drugs.

Effects of Some Natural Products of Traditional Chinese Medicine and Their Derivatives on Gastric Cancer Through the PD-L1 Pathway

Astragalus membranaceus (Fisch)

Astragalus membranaceus is a herb with antitumor effects against cancers of the digestive tract.²⁴ Astragaloside IV (AS-IV) is one of the major compounds extracted from the traditional Chinese medicine Astragalus membranaceus. AS-IV has been shown to be a promising anticancer drug for gastric cancer, which can exert antitumor effects by hindering gastric cancer-associated fibroblast, an inducer of tumor cell growth.²⁵ According to an experimental study by Wei Liu et al, astragaloside can exert an inhibitory effect on epithelial–mesenchymal transition and angiogenesis, which is achieved by increasing the expression of miR-195-5p and inducing miR-195-5p to target and negatively regulate the expression of PD-L1, thereby generating a potential therapeutic effect on gastric cancer.²⁶ Another study showed that the Chinese herbal formula buzhongyiqi soup containing astragalus inhibited the expression of PD-L1 in gastric cancer through the PI3 K/AKT pathway and directly promoted the proliferation and activation of T lymphocytes. In addition, the study showed that tonifying Chinese herbal formula can reduce the proportion of PD-1+ Treg cells, suggesting that it can repair the already damaged immune system to a certain extent.²⁷ Based on its significance in gastric, rectal, colon, and pancreatic cancers, astragalus may play an important role in the future development of anticancer drugs for cancers of the digestive tract.

Coptis chinensis Franch

Coptis chinensis Franch. is a commonly used antitumor drug.²⁸ Berberine (BBR), an alkaloid derived from Coptis chinensis Franch, has been used as a therapeutic agent in the treatment of cancer, bacterial infections, diabetes, and cardiovascular and inflammatory diseases.^29-32 Berberine has been shown to have minimal cytotoxic effects on healthy cells, but it has antiproliferative effects on cancer cells (eg, breast, liver, and CRC cells).^33,34 In gastric cancer animal experiments, Yang Liu et al showed that BBR could enhance the sensitivity of tumor cells to cocultured T cells by reducing the level of PD-L1 in cancer cells. Furthermore, berberine exerts antitumor effects by enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells and regulatory T lymphocytes (Tregs). Berberine also triggers PD-L1 degradation via a ubiquitin (Ub)/proteasome-dependent pathway.³⁵ Therefore, Liu's experiment conducted related research on the antitumor mechanism of berberine and confirmed that berberine is a small-molecule immune checkpoint inhibitor that can be used for cancer treatment. This is good news for the development of immune checkpoint inhibitors for digestive tract cancers such as gastric cancer. Meanwhile, it has been shown that herbal formulas containing Rhizoma Coptidis exert antitumor effects by decreasing IL-6/JAK/STAT3-mediated PD-L1 activity as well as the drug sensitivity of gastric cancer cells by regulating the expression of 6-O-methylguanine-DNA methyltransferase.^36,37

Quercetin

Quercetin is a natural flavonoid extracted from the traditional Chinese medicine rutin. It has a wide range of sources and can be extracted from the flowers, leaves, and fruits of many plants. It has been shown that quercetin exerts an anticancer effect in gastric and pancreatic cancer.^38,39

Li et al identified potential active compounds through network pharmacology, molecular docking, and MMPBSA technology and used MST, cell research, and enzyme activity analysis to screen out the active ingredient quercetin in the traditional Chinese medicine compound GuiQiBaizhu, which inhibits HER2 activity. The PI3K/AKT pathway acts on PD-L1. Although this was a network pharmacology study, it verified and confirmed that quercetin can be used for gastric cancer treatment through the PD-L1 pathway.⁴⁰ However, given the lack of animal experiments and other experimental verifications, there are still gaps in the research on the effects of quercetin on PD-L1. Although there is a lack of sufficient evidence, a number of scholars have conducted research on quercetin in the context of digestive tract cancers, especially gastric cancer, and it is worth exploring whether quercetin can be applied as an immune checkpoint inhibitor in the future.

Ligustrum lucidum Ait

Oleanolic acid is a natural triterpenoid compound abundantly isolated from the traditional Chinese medicine Ligustrum lucidum Ait.⁴¹ According to current literature, oleanolic acid can effectively protect blood vessels, improve blood circulation, and play an anti-fatigue role, but it has also been proven to have a variety of anticancer effects.⁴²

Experiments by Lu et al showed that oleanolic acid blocked the IL-1β/NF-κB/TET3 axis in gastric cancer cells, leading to DNA hypomethylation and PD-L1 downregulation. Oleanolic acid is also used as an epigenetic modulator of immunotherapy or involved in the adjuvant treatment of gastric cancer. This study showed that oleanolic acid eliminated IL-1β-stimulated PD-L1 expression and restored the sensitivity of gastric cancer cells to the killing effect of cytotoxic T lymphocytes.⁴³ Overall, oleanolic acid has great potential as an immunomodulatory option to combat gastric cancer.

Paclitaxel

Paclitaxel, a diterpenoid alkaloid, is one of the most efficacious antitumor natural products. It was first obtained by American scientists Wani and Wall in 1967 from the bark of Pacific yew, Taxus brevifolia Nutt.⁴⁴ Paclitaxel has been used to treat prostate cancer, advanced breast cancer, pancreatic cancer, melanoma, non-small cell lung cancer, gastric adenocarcinoma, and many other cancers.^45-47 There are no studies investigating the direct action of paclitaxel on PD-L1, but a study by JinLing Yu et al found that PD-L1 monoclonal antibody-modified nanoliposomes containing a combination of paclitaxel and a P-gp transporter inhibitor were therapeutically effective in multidrug-resistant gastric cancer.⁴⁸ In addition, interestingly, a clinical study by Sasaki et al showed that receiving anti-PD-1 therapy first may improve tumor response to paclitaxel plus RAM, thereby improving the survival cycle of patients with advanced gastric cancer.⁴⁹

Effects of Some Natural Products of Traditional Chinese Medicine and Their Derivatives on Colorectal Cancer via the PD-L1 Pathway

Astragalus membranaceus

Astragalus membranaceus is a classic traditional Chinese medicine that is widely used for the treatment of inflammatory diseases, tumors, and various cardiovascular diseases, given its free radical-scavenger activity and neuroprotective effects. PG2 is a natural product extracted from the traditional Chinese medicine Astragalus membranaceus.⁵⁰ It is a botanical drug that is mostly composed of Astragalus polysaccharides. Hsu-Liang Chang et al found that PG2 extracted from Astragalus membranaceus downregulated PD-L1 expression through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase beta-1 (p70S6 K) pathway, thereby exerting an antitumor effect.⁵¹ Cycloastragenol is a potent active molecule in Astragalus.⁵² It has antiviral, antibacterial, anti-inflammatory, and other pharmacological effects.^53,54 The study by Deng et al confirmed the specific mechanism by which cycloastragenol inhibits the growth of colon cancer by enhancing the antitumor immunity of CD8+ T cells mainly through the inhibition of cathepsin B-mediated degradation of major histocompatibility complex I.⁵⁵ The combination of cycloastragenol and PD-1 antibody has been shown to promote antigen presentation in cancer cells on the one hand and to alleviate the depletion of CD8+ T cells on the other hand. In addition, the combination of cycloastragenol and PD-1 antibody has been shown to have superior antitumor effects.

Salvia plebeia R.Br

Salvia plebeia R.Br comes from traditional Chinese medicine and exhibits anti-inflammatory and antiviral properties.^56-58 Jang-Gi Choi et al demonstrated that Salvia miltiorrhiza extract, a constituent of Salvia miltiorrhiza, blocked PD-1/PD-L1 interactions and enhanced T-cell-mediated antitumor activity in a concentration-dependent manner.⁵⁹ In addition, cosmosiin in Salvia miltiorrhiza has a strong effect on blocking PD-1/PD-L1. Song et al demonstrated that Salvia miltiorrhiza Bunge aqueous extract inhibited Cox2-mediated PGE2 release, thereby remodeling the tumor inflammatory microenvironment, resulting in diminished infiltration of tumor-associated macrophages and enhanced infiltration and killing of CD8+ T cells.⁶⁰ Furthermore, Salvia miltiorrhiza Bunge aqueous extract in combination with anti-PD-L1 reduced PD-L1 expression on tumor-associated macrophages. Salvia miltiorrhiza has great potential as an anticancer Chinese medicine, which necessitates in-depth research.

Camptothecin

Camptothecin was first discovered and extracted by Wall et al in 1966.⁶¹ Its source is the Chinese endemic plant Camptothecin. Since its discovery, camptothecin has attracted much attention worldwide for its unique anticancer mechanism.^62,63 Camptothecin has been shown to be effective against a variety of cancers such as stomach, rectal, esophageal, and breast cancers. Many scholars have structurally modified Camptothecin and synthesized a variety of active derivatives, some of which have entered clinical applications. For example, irinotecan and topotecan have entered clinical applications in Japan and the United States, respectively. In a study by Deepa Bedi et al, it was proposed that camptothecin acts on the NF-kB signaling pathway to upregulate PD-L1 expression compared with other drugs.⁶⁴ That study examined the anticancer mechanism and stoichiometric concentrations of camptothecin, which may be useful for the clinical application of camptothecin and its derivatives.

Glycyrrhiza uralensis Fisch

Glycyrrhiza uralensis Fisch. is an ancient herb with powerful pharmacological activities, including anticancer, anti-inflammatory, and antioxidant activities, according to modern pharmacological studies.⁶⁵ The medicinal value of licorice is attributed to the flavonoid and triterpenoid saponin bioactive components of licorice. Licochalcone A is a novel flavonoid isolated from licorice root.⁶⁶ Current studies have shown that Licochalcone A acts on different types of tumors by different mechanisms. Experiments by Liu et al verified that LCA inhibited PD-L1 expression in colon cancer by suppressing the interaction between p65 and Ras. It also enhanced the activity of cytotoxic T lymphocytes and restored the ability to kill tumor cells.⁶⁷ Meanwhile, Li et al developed leukocyte membrane-coated poly (lactic-co-glycolic acid) glycyrrhetinic acids, which can synergize with ferredoxinol and anti-PD-L1 to synergistically improve T-cell immune responses to leukemia and colorectal tumors, resulting in enhanced targeting and tumor-homing capacity and reduced in-vivo toxicity.⁶⁸ Experimental studies have demonstrated that the combined therapy of Gegen Qinlian decoction and anti-mouse PD-1, which includes licorice, exhibits enhanced antitumor effects compared to individual treatments. Licorice, a herb with a rich historical background, warrants further investigation into its antitumor properties.

Curcuma longa L

Curcumin is an extract from the rhizome of turmeric, which is used in Chinese medicine for pain relief and other applications. Modern research has found that curcumin has a variety of biological activities, such as antioxidant, anti-inflammatory, and antitumor properties.⁶⁹ There are also various studies showing the effectiveness and safety of curcumin in the prevention and treatment of various human diseases.⁷⁰ Qin Tong et al demonstrated that curcumin enhanced the killing effect of T cells on tumor cells by inhibiting PD-L1.⁷¹ Curcumin was found to inhibit PD-L1 expression and promote tumor-cell killing by T cells by regulating miR-206 in colon cancer and providing a barrier to the JAK/STAT3 signaling pathway. Paul Dent et al validated that curcumin + sildenafil enhanced the efficacy of 5-fluorouracil in CT26 colorectal tumors. In the experiment, it was found that prior exposure of established CT26 tumors to curcumin + sildenafil significantly enhanced the efficacy of the subsequently administered anti-PD-1 antibody.²² Overall, curcumin is promising and has the potential to be an effective neoadjuvant therapy for colon cancer. Curcumin has a high safety profile with few adverse effects.⁷⁰

Ziziphus jujuba Mill

Ziziphus jujuba Mill., a herbal medicine from natural fruits, has high nutritional and medicinal value. An animal study by Jing et al showed that oral administration of ultrafine septoria powder was able to improve the gastrointestinal microbiota of mice through enriched populations of Trichoderma spp. and Flavobacterium tumefaciens, enhance the production of short-chain fatty acids, and improve tumor immune infiltration and systemic immunity, which together contributed to the antitumor efficiency of αPD-L1 in vivo.⁷² The study by Nan Jing et al contributed to the development of dietary interventions for cancer immunotherapy using natural nutrients, and it is worth trying to see whether combining nutritional interventions during anti-PD-L1 can be effective in improving antitumor effects.

Actinidia eriantha

The root of Actinidia eriantha is a traditional Chinese medicine and has been widely used in treating various malignant tumors. A. eriantha polysaccharide (AEPS) is the active component of A. eriantha and has been reported to have antitumor effects. JinXia Liu et al studied the efficacy and mechanism of introducing anti-PD-1 therapy combined with AEPS therapy into rectal cancer-xenograft mice. Through experiments, the authors found that the combined therapy inhibited tumor growth and prolonged the survival rate of the mice. At the same time, the immunoregulatory cytokines TNFα and IFNγ were significantly increased.⁷³ That experiment explored AEPS combined with anti-PD-1 therapy, which may provide a reference for the future AEPS combined therapy as adjuvant therapy.

Reynoutria japonica Houtt

Resveratrol is mainly derived from the rhizome extract of the Chinese herbal medicine Reynoutria japonica Houtt. Resveratrol has some other biological activities, such as anti-aging, antibacterial, antioxidant, and immunomodulatory properties. Piceatannol is a compound with a chemical structure similar to resveratrol, which helps prevent cancer, heart disease, and neurological disorders. In a pilot study, Justin Lucas et al demonstrated that resveratrol and leucovorin could regulate PD-L1 expression in breast and CRC cells.⁷⁴ When resveratrol was used in combination with leucovorin, it caused synergistic upregulation of PD-L1 in some cell lines. PD-L1 was most clearly induced in Cal51 triple-negative breast cancer and SW620 colon cancer cells by the combination of drugs, and this was mediated by NF-κB transcription. This approach, by causing upregulation of PD-L1, can sensitize such cells, which are originally insensitive to PD-L1, to PD-L1 inhibitors and develop new therapeutic modalities.

Cordyceps sinensis (BerK.) Sacc

Cordycepin was initially extracted from Cordyceps militaris, marking it as the pioneering nucleoside antibiotic to be isolated from fungi.⁷⁵ Since its discovery, cordycepin has been shown to be effective in a number of cancers, including lung cancer⁷⁶ and ovarian cancer.⁷⁷ Recently, a study by Wu et al has confirmed that cordycepin has the potential to enhance the antitumor effects in CRC, and a strong antitumor effect has been demonstrated in a CRC model, with the reduction of PD-L1 expression on tumor cells as the underlying cellular mechanism. It has also been found that cordycepin can directly hinder the proliferation and migration of CRC cells, promote cell apoptosis, and induce cell cycle arrest.⁷⁸

Artemisia annua L

Artemisia has been used to treat fever, and the extract of artemisinin and artemisinin derivatives from Artemisia are a first-line treatment for malaria. The active compounds of artemisinin and its derivatives have been shown to have toxic effects on human cancer cells. The study by Sun et al has confirmed that artemisinin inhibits chondroitin sulfate synthase 1 activity and reduces liver metastasis of rectal colon cancer, and this inhibition is specific. Concurrent artemisinin and anti-PD1 combination can co-treat CRC liver metastases.⁷⁹ Dihydroartemisinin (DHA), an active metabolite of artemisinin, is one of the antimalarial drugs, and recent studies have demonstrated cytotoxicity against a variety of cancer cells in vitro. Recent findings confirm that DHA, one of only a few immunogenic cell death inducers, synergistically enhances the tumor immunogenicity of oxaliplatin and thus enhances the efficacy of cancer immunotherapy. According to Han et al, coadministration of exogenous iron complex and DHA induces the production of more reactive oxygen species and produces a significant inhibitory effect on tumors in vivo.⁸⁰ By increasing tumor immunogenicity, the combination of DHA and Pyro-Fe sensitizes non-immunogenic colorectal tumors to anti-PD-L1 checkpoint blockade immunotherapy. These findings demonstrate the potential of using nanotechnology to repurpose artemisinin, its derivatives, and other drugs with excellent safety profiles for the treatment of cancer in combination with immune checkpoint blockers.

Panax ginseng C. A. Mey

Ginseng is widely used in traditional Chinese medicine and is considered to have a variety of values, including antitumor activity.⁸¹ Ginsenoside is one of the active ingredients extracted from ginseng. The combination of ginsenosides with rosmarinic acid with inhibitory effects on PD-1 and PD-L1 binding can further inhibit lung metastasis of colon cancer.⁸² Ginsenosides and rosmarinic acid have a better safety profile; do not damage the tissue structure of the liver, stomach, and colon; and reduce toxic effects on tumors while maintaining efficacy.

Koryo red ginseng is a traditional herb processed by steaming or drying ginseng and is used in East Asia to treat a variety of ailments, such as allergies, inflammation, and cancerous diseases.⁸³ During processing, the type and concentration of ginsenosides, a compound unique to ginseng, change, and polysaccharides, the most abundant compound in red ginseng, also undergo physical and chemical changes. LEE et al found that Korean Red Ginseng extract (RGE) inhibited PD-1/PD-L1 interaction and suppressed cell growth of CRC by enhancing the immune function of tumor-infiltrating CD8+ T cells in a coculture cell model. RGE significantly blocked the interaction between PD-1 and PD-L1. Korean Red Ginseng extract treatment significantly inhibited the growth of hPD-L1 MC38 xenograft tumors, increased the infiltration of CD8+ T cells into the tumors, and enhanced the production of Granzyme B.⁸⁴

Coriolus versicolor (L. ex Fr.) Quel

Coriolus versicolor (L. ex Fr.) Quel is widely used in Asian traditional medicine for its typical constituent polysaccharide peptide (PSP). PSPs are thought to have anticancer properties^85,86 and also have immunomodulatory properties.^87,88 Jian et al demonstrated that PSPs inhibited CRC proliferation by suppressing the expression of epidermal growth factor receptor and PD-L1.⁸⁹

Rhus chinensis Mill

Rhus chinensis Mill. is a Chinese herb with a variety of effects, including anticancer effects.⁹⁰ Triterpenoids of R. chinensis (TER), a constituent from Pentaphyllum officinale, was shown by Wang et al to inhibit tumor progression by regulating the expression of PD-L1 and significantly reduced mortality in mice.⁹¹ This study also evaluated the role of TER in the CT26 xenograft model and confirmed that TER exerted potential immunostimulatory activity in the CT26 xenograft model by modulating intratumoral infiltration of CD8+ T cells, such as modulating NK cells and CD4 + and CD8+ T cells in spleen, blood, and tumor tissues. In addition, the mechanisms by which TER inhibits tumor growth and modulates CRC antitumor immunity by increasing the infiltration of CD8+ T cells into the central region of the tumor have also been investigated. TER, a constituent from Pentaphyllum officinale, inhibit tumor progression by regulating the expression of PD-L1 and significantly reduce mortality in mice.

Conclusion and Outlook

The immune checkpoint PD-1/PD-L1 pathway plays a crucial role in promoting tumor immune escape by inducing the expression of immunosuppressive molecules and inhibiting T lymphocyte activation. In recent years, inhibitors targeting this pathway have emerged as a key approach in cancer therapy. FDA-approved immunotherapy strategies that disrupt PD-1 and PD-L1 binding, leading to upregulation of T-cells, have shown promise in clinical settings. While 5 classes of PD-L1 inhibitors are currently in use, the development of new immune checkpoint inhibitors remains a priority.

Natural products derived from traditional Chinese medicine show promise as a potential solution to the issue at hand. These products exhibit a range of effects, such as directly blocking PD-1/PD-L1 interactions, influencing PD-L1 expression, and serving as adjuvants alongside PD-1/PD-L1 inhibitors. As research progresses, the repertoire of anti-PD-L1 traditional Chinese medicines, extracts, and formulas continues to expand, leading to a deeper exploration of traditional Chinese medicine mechanisms against PD-L1. Nevertheless, the study of traditional Chinese medicine in anti-PD-L1 therapy is still in its early stages, with limited in-depth clinical investigations conducted thus far. In addition, there are many Chinese medicines that can treat gastric cancer and colon cancer, such as Codonopsis pilosula (Franch.) Nannf.,⁹² Scutellaria barbata D.Don,⁹³ Scleromitrion diffusum (Willd.) R. J. Wang,⁹⁴ Cremastra appendiculata (D.Don) Makino,⁹⁵ Sparganium stoloni erum, Buch. -Ham., and Curcuma phaeocaulis Valeton.⁹⁶ Relevant studies have shown that these herbs have obvious efficacy in gastric and colon cancers, but these herbs have not yet been included in the study of anti-PD-1/PD-L1 mechanism, which needs to be explored in depth.

In conclusion, we hope that this review will provide some insights into the mode of action and pathways of PD-L1, the role of traditional Chinese medicine and its natural products in gastric and rectal cancers, and their pharmacological mechanisms. At present, traditional Chinese medicine and its natural products have unique advantages as immune checkpoint inhibitors in the PD-L1 pathway. In this regard, hope that more researchers and doctors will devote more attention to this, conduct more studies and trials, and do more in-depth research.

Footnotes

Acknowledgments

We thank LetPub () for its linguistic assistance during the preparation of this manuscript.

Author Contributions

All authors contributed substantially to the article. CSC conceived and designed this paper. XHZ, SJW, LX, DMC, and TRZ summarized and analyzed the data. XHZ, MRZ, and ZCF drafted, revised, and edited the paper.

Declaration of Conflicting Interests

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

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

XingHui Zhu

References

Kalbasi

Ribas

. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25-39.

Han

Liu

. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.

Xu J, ed. Regulation of cancer immune checkpoints. Advances in Experimental Medicine and Biology; 2020.

. Tumor-associated macrophages regulate PD-1/PD-L1 immunosuppression. Front Immunol. 2022;13:874589. doi:10.3389/fimmu.2022.874589

Sugiura

Shimizu

Maruhashi

Okazaki

I-M

Okazaki

. T-cell-intrinsic and -extrinsic regulation of PD-1 function. Int Immunol. 2021;33(12):693-698.

Goodman

Patel

Kurzrock

. PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol. 2017;14(4):203-220.

Sugita

Fujimori

Ikeda

. Immuno-histological and-cytological examinations on distribution of newly reported co-stimulatory molecules in germinal center of human tonsils. Nippon Jibiinkoka Gakkai Kaiho. 2005;108(1):31-37. doi:https://doi.org/10.3950/jibiinkoka.108.31

Francisco

Sage

Sharpe

. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236(1):219-242. doi:10.1111/j.1600-065X.2010.00923.x

Tang

Chen

, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13:964442.

10.

Routy

Le Chatelier

Derosa

, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.

11.

Chai

Huang

. PD-L1 and survival in solid tumors: a meta-analysis. PLoS One. 2015;10(6):e0131403.

12.

Cha

Chan

Hsu

Hung

. Mechanisms controlling PD-L1 expression in cancer. Mol Cell. 2019;76(3):359-370.

13.

Ohaegbulam

Assal

Lazar-Molnar

Yao

Zang

. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24-33.

14.

Zheng

Niu

Zhu

. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21(1):28.

15.

Verma

Sharma

. Next generation sequencing-based emerging trends in molecular biology of gastric cancer. Am J Cancer Res. 2018;8(2):207-225.

16.

Zheng

Liu

, et al. Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 2014;26(1):104-111.

17.

Zhang

Dong

Liu

, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients. Sci Rep. 2016;6:37933. doi:10.1038/srep37933

18.

Liu

Wang

, et al. Prognostic significance of PD-L1 expression in patients with gastric cancer in East Asia: a meta-analysis. Onco Targets Ther. 2016;9:2649-2654. doi:10.2147/OTT.S102616

19.

Joshi

Badgwell

. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71(3):264-279.

20.

, et al. Relationship between the expressions of PD-L1 and tumour-associated fibroblasts in gastric cancer. Artif Cells Nanomed Biotechnol. 2019;47(1):1036-1042.

21.

Bray

Ferlay

Soerjomataram

Siegel

Torre

Jemal

. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424.

22.

Tong

. Curcumin inhibits colon cancer malignant progression and promotes T cell killing by regulating miR-206 expression. Clin Anat. 2024;37(1):2-11.

23.

Overman

McDermott

Leach

, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182-1191.

24.

Baxi

Yang

Gennarelli

, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. Br Med J. 2018;360:k793. doi:10.1136/bmj.k793

25.

Wang

Mou

Cui

, et al. Astragaloside IV inhibits cell proliferation of colorectal cancer cell lines through down-regulation of B7-H3. Biomed Pharmacother. 2018;102:1037-1044. doi:10.1016/j.biopha.2018.03.127

26.

Wang

Zhu

, et al. Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts. World J Gastroenterol. 2017;23(48):8512-8525.

27.

Liu

Chen

Wang

. Protective role of astragaloside IV in gastric cancer through regulation of microRNA-195-5p-mediated PD-L1. Immunopharmacol Immunotoxicol. 2021;43(4):443-451.

28.

Zhang

, et al. Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracile to inhibits gastric cancer progress via PD-1/PD- L1-dependent T cell immunization. Pharmacol Res. 2020;152:104623. doi:10.1016/j.phrs.2019.104623

29.

Liu

. Multifunctional epiberberine mediates multi-therapeutic effects. Fitoterapia. 2020;147:104771. doi:10.1016/j.fitote.2020.104771

30.

Wang

Tang

Guo

, et al. Research progress on the anti-tumor mechanism and reversal of multidrug resistance of Zuojin Pill and its main components, evodiamine and berberine. Nat Prod Commun. 2023;18(3). doi:10.1177/1934578X231161414

31.

Fan

, et al. Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions. Acta Pharm Sin B. 2020;10(3):447-461.

32.

Feng

Sureda

Jafari

, et al. Berberine in cardiovascular and metabolic diseases: from mechanisms to therapeutics. Theranostics. 2019;9(7):1923-1951.

33.

Ding

Tang

. Berberine as a promising anti-diabetic nephropathy drug: an analysis of its effects and mechanisms. Eur J Pharmacol. 2015;760:103-112. doi:10.1016/j.ejphar.2015.04.017

34.

Liu

Wang

Yang

Pan

Yang

Zang

. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes. PLoS One. 2011;6(6):e21416.

35.

Chidambara Murthy

Jayaprakasha

Patil

. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur J Pharmacol. 2012;688(1-3):14-21.

36.

Liu

Zhang

, et al. Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5. Acta Pharm Sin B. 2020;10(12):2299-2312.

37.

Feng

Xue

Huang

. Banxia xiexin decoction affects drug sensitivity in gastric cancer cells by regulating MGMT expression via IL-6/JAK/STAT3-mediated PD-L1 activity. Int J Mol Med. 2021;48(2):165.

38.

Feng

Xue

Huang

. Banxia Xiexin decoction inhibits the expression of PD-L1 through multi-target and multi-pathway regulation of major oncogenes in gastric cancer. Onco Targets Ther. 2021;14:3297-3307. doi:10.2147/OTT.S288442

39.

Xiang

, et al. Quercetin inhibits epithelial-mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial-mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells. Onco Targets Ther. 2017;10:4719-4729. doi:10.2147/OTT.S136840

40.

Shen

Wang

Guo

Zhang

. Quercetin inhibits the growth of human gastric cancer stem cells by inducing mitochondrial-dependent apoptosis through the inhibition of PI3K/Akt signaling. Int J Mol Med. 2016;38(2):619-626.

41.

Jin

, et al. Systematic insight into the active constituents and mechanism of Guiqi Baizhu for the treatment of gastric cancer. Cancer Sci. 2021;112(5):1772-1784.

42.

Cao

Wastney

Lachcik

Xiao

Weaver

Wong

. Both oleanolic acid and a mixture of oleanolic and ursolic acids mimic the effects of Fructus ligustri lucidi on bone properties and circulating 1,25-dihydroxycholecalciferol in ovariectomized rats. J Nutr. 2018;148(12):1895-1902.

43.

Ayeleso

Matumba

Mukwevho

. Oleanolic acid and its derivatives: biological activities and therapeutic potential in chronic diseases. Molecules. 2017;22(11):1915.

44.

Yang

, et al. Inhibition of NF-κB is required for oleanolic acid to downregulate PD-L1 by promoting DNA demethylation in gastric cancer cells. J Biochem Mol Toxicol. 2021;35(1):e22621.

45.

Wani

Taylor

Wall

Coggon

McPhail

. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971;93(9):2325-2327.

46.

Kang

Syed

. Atezolizumab (in combination with nab-paclitaxel): a review in advanced triple-negative breast cancer. Drugs. 2020;80(6):601-607.

47.

Hoff

Ervin

Arena

, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.

48.

Weber

D'Angelo

Minor

, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-384.

49.

Zhu

, et al. PD-L1 monoclonal antibody-decorated nanoliposomes loaded with paclitaxel and P-gp transport inhibitor for the synergistic chemotherapy against multidrug resistant gastric cancers. Nanoscale Res Lett. 2020;15(1):59.

50.

Sasaki

Kawazoe

Eto

, et al. Improved efficacy of taxanes and ramucirumab combination chemotherapy after exposure to anti-PD-1 therapy in advanced gastric cancer. ESMO Open. 2020;4(Suppl 2):e000775.

51.

Kuo

Chen

Chuang

, et al. Gene expression profiling and pathway network analysis predicts a novel antitumor function for a botanical-derived drug, PG2. Evid Based Complement Alternat Med. 2015;2015:917345. doi:10.1155/2015/917345

52.

Chang

Kuo

, et al. The extracts of Astragalus membranaceus overcome tumor immune tolerance by inhibition of tumor programmed cell death protein ligand-1 expression. Int J Med Sci. 2020;17(7):939-945.

53.

Song

Liu

, et al. Study on the biotransformation and activities of astragalosides from astragali radix In Vitro and In Vivo. J Agric Food Chem. 2023;71(46):17924-17946.

54.

Deng

Chen

Wang

, et al. Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice. Int Immunopharmacol. 2019;74:105682. doi:10.1016/j.intimp.2019.105682

55.

Dou

, et al. Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia. Acta Pharmacol Sin. 2020;41(8):1025-1032.

56.

Deng

Zhou

Wang

, et al. Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8T cells via inhibiting MHC-I degradation. J Immunother Cancer. 2022;10(10):e004874.

57.

Zou

Zhao

, et al. Anti-inflammatory sesquiterpenoids from the traditional Chinese medicine Salvia plebeia: regulates pro-inflammatory mediators through inhibition of NF-κB and Erk1/2 signaling pathways in LPS-induced Raw264.7 cells. J Ethnopharmacol. 2018;210:95-106. doi:10.1016/j.jep.2017.08.034

58.

Bang

Quy Ha

Lee

Shim

. Antiviral activities of compounds from aerial parts of Salvia plebeia R. Br. J Ethnopharmacol. 2016;192:398-405. doi:10.1016/j.jep.2016.09.030

59.

Bang

TKQ

Lee

Shim

. Anti-influenza effect of the major flavonoids from Salvia plebeia R.Br. via inhibition of influenza H1N1 virus neuraminidase. Nat Prod Res. 2018;32(10):1224-1228.

60.

Choi

Kim

, et al. Anticancer effect of Salvia plebeia and its active compound by improving T-cell activity via blockade of PD-1/PD-L1 interaction in humanized PD-1 mouse model. Front Immunol. 2020;11:598556. doi:10.3389/fimmu.2020.598556

61.

Song

Qian

Zhang

, et al. Salvia mitiorrhiza Bunge aqueous extract attenuates infiltration of tumor-associated macrophages and potentiates anti-PD-L1 immunotherapy in colorectal cancer through modulating Cox2/PGE2 cascade. J Ethnopharmacol. 2023;316:116735. doi:10.1016/j.jep.2023.116735

62.

Wall

. Camptothecin and taxol: discovery to clinic. Med Res Rev. 1998;18(5):299-314.

63.

Pommier

. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6(10):789-802.

64.

Xie

Lin

Liu

, et al. Ultrasound-responsive nanobubbles contained with peptide-camptothecin conjugates for targeted drug delivery. Drug Deliv. 2016;23(8):2756-2764.

65.

Bedi

Henderson

Manne

Samuel

. Camptothecin induces PD-L1 and immunomodulatory cytokines in colon cancer cells. Medicines (Basel). 2019;6(2):51.

66.

Yang

Wang

Yuan

Liu

. The pharmacological activities of licorice. Planta Med. 2015;81(18):1654-1669.

67.

Hsieh

Guo

, et al. Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem Biophys Res Commun. 2004;322(1):263-270.

68.

Liu

Xing

, et al. Licochalcone A inhibits proliferation and promotes apoptosis of colon cancer cell by targeting programmed cell death-ligand 1 via the NF-κB and Ras/Raf/MEK pathways. J Ethnopharmacol. 2021;273:113989. doi:10.1016/j.jep.2021.113989

69.

Jia

, et al. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis. 2019;10(6):415.

70.

Zhu

Sanidad

Sukamtoh

Zhang

. Potential roles of chemical degradation in the biological activities of curcumin. Food Funct. 2017;8(3):907-914.

71.

Kocaadam

Şanlier

. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr. 2017;57(13):2889-2895.

72.

Dent

Booth

Roberts

Poklepovic

Hancock

. (Curcumin + sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo. J Cell Physiol. 2020;235(10):6862-6874.

73.

Jing

Wang

Zhuang

Jiang

Liu

. Ultrafine jujube powder enhances the infiltration of immune cells during anti-PD-L1 treatment against murine colon adenocarcinoma. Cancers (Basel). 2021;13(16):3987.

74.

Wang

Jin

Shen

. Actinidia eriantha polysaccharide and PD1-antibody combination therapy enhances antitumor efficacy in colorectal cancer-xenograft mice. Onco Targets Ther. 2021;14:1239-1248. doi:10.2147/OTT.S294253

75.

Lucas

Hsieh

Halicka

Darzynkiewicz

. Upregulation of PD-L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300-mediated NF-κB signaling. Int J Oncol. 2018;53(4):1469-1480.

76.

Cunningham

Manson

Spring

Hutchinson

. Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) Link. Nature. 1950;166(4231):949.

77.

Wei

Yao

Jiang

, et al. Cordycepin inhibits drug-resistance non-small cell lung cancer progression by activating AMPK signaling pathway. Pharmacol Res. 2019;144:79-89. doi:10.1016/j.phrs.2019.03.011

78.

Jang

Yang

Hwang

, et al. Cordycepin inhibits human ovarian cancer by inducing autophagy and apoptosis through Dickkopf-related protein 1/β-catenin signaling. Am J Transl Res. 2019;11(11):6890-6906.

79.

Fang

Chen

, et al. Cordycepin remodels the tumor microenvironment of colorectal cancer by down-regulating the expression of PD-L1. J Cancer Res Clin Oncol. 2023;149(19):17567-17579.

80.

Sun

Zhao

Fan

, et al. CHSY1 Promotes CD8+ T cell exhaustion through activation of succinate metabolism pathway leading to colorectal cancer liver metastasis based on CRISPR/Cas9 screening. J Exp Clin Cancer Res. 2023;42(1):248.

81.

Han

Duan

Chan

Lin

. Co-delivery of dihydroartemisinin and pyropheophorbide-iron elicits ferroptosis to potentiate cancer immunotherapy. Biomaterials. 2022;280:121315. doi:10.1016/j.biomaterials.2021.121315

82.

Mancuso

Santangelo

. Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol. 2017;107(Pt A):362-372.

83.

Liu

Deng

Zhu

, et al. Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis. Acta Pharmacol Sin. 2024;45(1):193-208. doi:https://doi.org/10.1038/s41401-023-01158-8

84.

Hyun

Kim

Seo

, et al. Physiological and pharmacological features of the non-saponin components in Korean red Ginseng. J Ginseng Res. 2020;44(4):527-537.

85.

Lee

Yang

Cho

Choi

Chung

. Antitumor effect of Korean red Ginseng through blockade of PD-1/PD-L1 interaction in a humanized PD-L1 knock-in MC38 cancer mouse model. Int J Mol Sci. 2023;24(3):1894.

86.

Sullivan

Smith

Rowan

. Medicinal mushrooms and cancer therapy: translating a traditional practice into western medicine. Perspect Biol Med. 2006;49(2):159-170.

87.

Zhong

Yan

Lam

Yao

Bian

. Coriolus Versicolor and Ganoderma Lucidum related natural products as an adjunct therapy for cancers: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2019;10:703. doi:10.3389/fphar.2019.00703

88.

Wang

Liu

Zhou

Long

Zhou

Bao

. Immunomodulatory effect of APS and PSP is mediated by Ca2+-cAMP and TLR4/NF-κB signaling pathway in macrophage. Int J Biol Macromol. 2017;94(Pt A):283-289.

89.

Jedrzejewski

Piotrowski

Wrotek

Kozak

. Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats. J Therm Biol. 2014;44:1-4. doi:10.1016/j.jtherbio.2014.06.003

90.

Jian

Zhicheng

Shubai

. Polysaccharide peptide induced colorectal cancer cells apoptosis by down-regulating EGFR and PD-L1 expression. Iran J Pharm Res. 2022;21(1):e123909.

91.

Djakpo

Yao

. Rhus chinensis and Galla Chinensis–folklore to modern evidence: review. Phytother Res. 2010;24(12):1739-1747.

92.

Wang

Zhu

Wang

Tao

. Triterpenoids of Rhus chinensis supressed colorectal cancer progress by enhancing antitumor immunity and CD8 + T cells tumor infiltration. Nutr Cancer. 2022;74(7):2550-2564.

93.

Bailly

. Anticancer properties of Lobetyolin, an essential component of Radix Codonopsis (Dangshen). Nat Prod Bioprospect. 2021;11(2):143-153.

94.

Yin

You

. Molecular mechanism of anti-colorectal cancer effect of Hedyotis diffusa Willd and its extracts. Front Pharmacol. 2022;13:820474. doi:10.3389/fphar.2022.820474

95.

Zhang

Wei

, et al. Isolation, purification, structural characteristics, pharmacological activities, and combined action of Hedyotis diffusa polysaccharides: a review. Int J Biol Macromol. 2021;183:119-131. doi:10.1016/j.ijbiomac.2021.04.139

96.

Liu

Tang

, et al. A review of Cremastra appendiculata (D.Don) Makino as a traditional herbal medicine and its main components. J Ethnopharmacol. 2021;279:114357. doi:10.1016/j.jep.2021.114357

Application of Traditional Chinese Medicine in Inhibiting the PD-1/PD-L1 Pathway in the Treatment of Gastric and Colon Cancers

Abstract

Keywords

Effects of Some Natural Products of Traditional Chinese Medicine and Their Derivatives on Gastric Cancer Through the PD-L1 Pathway

Astragalus membranaceus (Fisch)

Coptis chinensis Franch

Quercetin

Ligustrum lucidum Ait

Paclitaxel

Effects of Some Natural Products of Traditional Chinese Medicine and Their Derivatives on Colorectal Cancer via the PD-L1 Pathway

Astragalus membranaceus

Salvia plebeia R.Br

Camptothecin

Glycyrrhiza uralensis Fisch

Curcuma longa L

Ziziphus jujuba Mill

Actinidia eriantha

Reynoutria japonica Houtt

Cordyceps sinensis (BerK.) Sacc

Artemisia annua L

Panax ginseng C. A. Mey

Coriolus versicolor (L. ex Fr.) Quel

Rhus chinensis Mill

Conclusion and Outlook

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References