Targeting GPR34 in damage-associated macrophages enhances anti-tumor immunity and the efficacy of Surufatinib in pancreatic cancer

Abstract Tumor-associated macrophages (TAMs) are pivotal in the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). The efficacy of targeting the CSF-1/CSF-1R axis in PDAC remains uncertain. Using single-cell RNA sequencing on specimens from patients treated with Surufatinib plus chemotherapy, we identified a distinct subset of damage-associated macrophages (DAMs) characterized by high GPR34 expression. In Gpr34 ΔLyz2 mouse models and in vitro co-cultures, GPR34+ macrophages responded to tissue damage by releasing lysophosphatidylserine (LysoPS), which enhanced CXCL16 secretion and efferocytosis. This efferocytosis promoted MHC-I degradation via the macrophage lysosomal pathway, leading to CD8+ T cell exhaustion. Combining a GPR34 antagonist with chemotherapy and surufatinib significantly enhanced anti-tumor responses in preclinical models. These findings identify GPR34 as a promising immune therapeutic target.