FOLR2+ tumor-associated macrophages drive metastatic microenvironment remodeling and lymphatic dissemination in colorectal cancer

The accumulation of specialized tumor-associated macrophage (TAM) subpopulations within the immune-excluded microenvironment critically drives colorectal Cancer (CRC) progression and therapeutic resistance. Although the FOLR2⁺ macrophage lineage has been identified in the niche of several malignancies, the mechanisms by which tumor cells regulate FOLR2 expression and the pathways through which these cells facilitate metastasis are not well understood. Herein, we found that FOLR2 expression defines a distinct macrophage state associated with advanced clinical stages and unfavorable outcomes in CRC. Tumor cells induce FOLR2 expression via activation of Akt signaling, which is essential for establishing and sustaining the M2-like functional phenotype of TAMs. FOLR2⁺ TAMs facilitate tumor cell migration, invasion, and lymphangiogenesis, and they preferentially localize to collagen-rich perivascular niches within the tumor microenvironment. Mechanistically, FOLR2 drives PLA2G7 production to mediate extracellular matrix remodeling and tumor cell motility, but FOLR2 facilitates lymphangiogenesis through a distinct, PLA2G7-independent mechanism. In vivo, this dual-track cascade was successfully recapitulated: pharmacological inhibition of PLA2G7 with darapladib blunted stromal Collagen deposition and primary tumor growth, whereas FOLR2 silencing uniquely suppressed peritumoral lymphangiogenesis and popliteal lymph node metastasis. Bioinformatic analysis further revealed that high co-expression of FOLR2 and PLA2G7 correlates with elevated TIDE scores and increased IC50 values to oxaliplatin and targeted agents, predicting intrinsic immune evasion and therapy resistance. Together, this work establishes FOLR2 as a pivotal regulator of the CRC stroma and suggest that therapeutic strategies targeting the FOLR2/PLA2G7 axis could improve clinical outcomes by disrupting the supportive metastatic niche.