Unveiling and harnessing: the tumor microenvironment in RAS/MAPK pathway-targeted therapy

Abstract

The RAS/mitogen-activated protein kinase (MAPK) pathway is a pivotal oncogenic driver in numerous malignancies, most prominently pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung cancer, and melanoma. The emergence of direct KRAS inhibitors, pan-RAS inhibitors, and agents targeting downstream signaling pathways (including MEK and ERK) has profoundly reshaped the therapeutic landscape. However, durable clinical responses remain scarce, owing to profound, rapid, and adaptive resistance mechanisms that extend far beyond tumor cell-intrinsic pathways. Over the past five years, accumulating evidence has unequivocally established that the tumor microenvironment (TME)—particularly its immune components—plays a key role in driving this resistance. This review synthesizes recent advances in understanding how specific TME constituents, including immune cells, cancer-associated fibroblasts (CAFs), and the extracellular matrix (ECM), interact with tumor cells to promote escape from pathway inhibition. We examine bidirectional signaling induced by therapy, consequent tumor cell plasticity, and the formation of a protective niche. Finally, we outline rational combination strategies that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.