The MAPK pathway as a pharmacological target to reprogram cancer-associated fibroblasts and disrupt the stromal shield.

The tumor microenvironment is a complex and dynamic ecosystem composed of a heterogeneous population of non-malignant cells, an extracellular matrix, and diverse soluble factors. Collectively, these elements orchestrate a pro-tumorigenic niche that supports tumor initiation, progression, and metastasis. Within this ecosystem, stromal cancer-associated fibroblasts (CAFs) represent a key cellular component that maintains the structural and functional integrity of the tumor-supportive microenvironment. Although tumor cells are known to actively recruit and educate fibroblasts toward a CAF phenotype, the molecular mechanisms underlying CAF differentiation and subsequent CAF-tumor crosstalk remain unclear. Recent evidence suggests that the mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in these processes by regulating CAF differentiation and its complex interactions with malignant and immune cells. Activation of MAPK signaling in CAFs and tumor cells not only correlates with tumor progression and immune evasion but also facilitates the establishment of therapy-resistant niches through intercellular reactivation of oncogenic signaling pathways. In this review, we delineate the pivotal roles of MAPK signaling in regulating CAF phenotypes, tumor cell behavior, and CAF-tumor crosstalk. We also discuss the therapeutic potential of targeting the MAPK signaling pathway to overcome the limitations of current anti-cancer strategies.