Collagen-mediated pro-tumorigenic MAPK activation drives stromal-immune reprogramming in solid cancers.

INTRODUCTION: Intratumoral collagen deposition is a hallmark of solid cancers and plays a critical role in shaping the tumor microenvironment (TME). This study aimed to characterize the clinical and molecular implications of collagen deposition and elucidate its role in modulating TME components and signaling pathways. METHODS: In this research, we analyzed transcriptomic data from public databases and our in-house clinical samples to expore the correlation between collagen deposition and TME features. In addition, the findings were validated through in vitro and in vivo assays. RESULTS: We found that high levels of intratumoral collagen deposition were related to poor clinical outcomes and advanced tumor stages in gastric cancer. Collagen deposition showed strong positive correlations with the abundance of vascular endothelial cells and M2-polarized macrophages, suggesting its role in promoting angiogenesis and immunosuppression. In addition, the correlations between collagen deposition and endothelial cells as well as M2-polarized macrophages were also confirmed in lung cancer. Moreover, pathway analysis revealed that collagen activated the MAPK signaling pathway, and in vitro and in vivo functional assays confirmed that collagen-mediated MAPK activation enhanced tumor cell invasion, angiogenesis, and M2 macrophage polarization. CONCLUSION: Our findings demonstrate that intratumoral collagen deposition is a key regulator of the TME in gastric cancer, promoting tumor progression through MAPK signaling pathway activation. These results demonstrate the promise of collagen as both a prognostic indicator and a therapeutic target, offering fresh perspectives on the underlying mechanisms of TME remodeling and tumor progression across various solid tumors.