The mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in regulating a number of cellular processes, including proliferation, differentiation, apoptosis, and cellular responses to stress. In cancer, abnormal activation of some or all pathways of the MAPK cascade, particularly the RAS/RAF/MEK/ERK and p38/JNK signaling pathways, is common across many cancers as well as in an equal or disproportional measure in tumor initiation and progression. In the context of the tumor microenvironment (TME), the MAPK pathway facilitates complex interactions between cancer cells, stroma, and immune and endothelial cells. These interactions allow for elements of tumorigenesis, such as driving angiogenesis, immune suppression, and remodeling of the extracellular matrix, to all contribute to tumor survival and invasion. Additionally, MAPK signaling programs the response to cytokines and growth factor secretion by the TME beyond direct cellular responses, ultimately remodeling the TME in a favorable way for tumorigenesis. While targeting components of MAPK-related pathways has shown promise in the clinic, intrinsic and acquired resistance continues to develop in response to drug therapy composed of compensatory convoluted signaling, the activation of alternate signaling pathways, and TME-induced secondary feedback response. Recent data demonstrate that immune- and stroma-derived signals within the TME can sustain MAPK activity even under pharmacologic inhibition, providing the complexity of achieving durable therapeutic responses. As a result, it is crucial to gain consideration of the connections between MAPK signaling and the TME that may impart for sensitive strategies to elicit sustained drug-resistant treatment responses. Integrative therapies that incorporate MAPK inhibitors in conjunction with immunotherapy approaches, anti-angiogenic therapies, or metabolic modulators are also an important therapeutic strategy to elicit these adaptive pathways. This review will summarize our current understanding of the complex role of MAPK signaling in the TME, as well as propose broad ideas and potential future manipulation of MAPK-coordinated TME approaches for novel, durable cancer therapies.
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