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. The detailed mechanism of how hypoxia and acidity promote immune exclusion remains unclear. The authors here identify that GPR4, a proton sensor, induces immune exclusion by facilitating collagen alignment via upregulating LOXL2. Furthermore, inhibiting LOXL2 or GPR4 signal pathway alleviates immune exclusion.