Apoptotic Cancer Cell-Primed Cancer-Associated Fibroblasts Suppress Immunosuppressive Macrophages via WISP-1-Integrin...

Cell death within the tumor microenvironment (TME) plays a pivotal role in shaping tumor-specific immunity. The dynamic interplay between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) is central to tumor progression and immune regulation. Here, we show that conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells selectively impairs the survival of M2-like macrophages, induces apoptosis, and promotes their reprogramming toward an M1-like phenotype. These effects were abrogated by knockdown of Wnt-induced signaling protein 1 (WISP-1) in CAFs, identifying WISP-1 as a key paracrine effector. Mechanistically, WISP-1 signals through the integrin α5β3-STAT1 axis to mediate M2 TAM apoptosis and M1-like reprogramming. In vivo, intratumoral injection of CM derived from CAF exposed to apoptotic 344SQ cells reduced overall TAM density, decreased the proportion of M2-like TAMs, and promoted their reprogramming toward an M1-like phenotype, accompanied by STAT1 activation in M2 TAMs. This phenotypic shift was associated with increased infiltration of cytotoxic CD8⁺ T cells and reduced accumulation of regulatory T cells within the tumor. Notably, these effects were abolished by either depletion of WISP-1 from the CM or pharmacological inhibition of STAT1 following recombinant WISP-1 administration. Collectively, our findings identify the WISP-1-integrin α5β3-STAT1 axis as a novel therapeutic target for TAM reprogramming and tumor suppression in lung cancer.