GPR4 promotes immune exclusion in colon cancer through LOXL2-mediated extracellular matrix remodeling

Immune exclusion is associated with adverse prognosis in tumors, and this phenomenon may be facilitated by a physical barrier constituted by the extracellular matrix (ECM). Hypoxia and acidity promote immune exclusion, however the detailed mechanism remains unclear. This study demonstrate that G-protein-coupled-receptor-4 (GPR4), as a proton sensor, induces immune exclusion in colon cancer by promoting collagen fiber alignment and deposition. Specifically, GPR4 facilitates collagen alignment via LOXL2 regulation and enhances collagen I by modulating TGF-β, both mediated by the JAK2/STAT3 pathway. We further validate our findings in a male animal model, observing that elevated GPR4 expression in colon cancer results in an immune-excluded microenvironment. Inhibition of the JAK2/STAT3 pathway and LOXL2 function effectively reverse immune exclusion and enhance immunotherapy efficacy. Collectively, our findings elucidate a mechanism of immune exclusion and propose a potential target for improving the therapeutic efficacy of immunotherapy through the remodeling of the tumor ECM.