LOXL2⁺ cancer-associated fibroblasts shape WNT signaling to drive chemoresistance and poor outcomes in colorectal cancer: Insights from multi-omics and epidemiological analyses

BACKGROUND: Cancer-associated fibroblasts (CAFs) critically influence colorectal cancer (CRC) progression and therapy response, yet their epidemiological and molecular heterogeneity remains underexplored. METHODS: We integrated bulk, single-cell, and spatial transcriptomic datasets from multiple CRC cohorts, together with patient-derived tissues and functional assays, to delineate CAF subtypes and their clinical significance. Epidemiological analyses were performed across independent cohorts to evaluate the association between CAF markers and patient outcomes. RESULTS: A myofibroblastic CAF (myCAF) subset characterized by high LOXL2 expression was consistently enriched in advanced and chemoresistant CRC samples. Multi-omics correlation analyses revealed that LOXL2⁺ CAFs activated WNT signaling in adjacent tumor cells, promoting stemness and drug resistance. Across population-based cohorts, elevated LOXL2 expression was independently associated with poor overall and disease-free survival, as confirmed by multivariate Cox regression. Spatial transcriptomics and immunofluorescence demonstrated close physical interaction between LOXL2⁺ CAFs and WNT5A-positive cancer cells. Functional inhibition or genetic silencing of LOXL2 and wnt5a in CAFs restored chemosensitivity in vitro and suppressed tumor growth in vivo. CONCLUSIONS: Our integrative epidemiological and experimental analyses identify LOXL2⁺ CAFs as a key stromal determinant of chemoresistance and poor prognosis in CRC. These findings highlight a clinically relevant stromal biomarker with potential for risk stratification and therapeutic targeting in colorectal cancer.