CXCL2 affects macrophage antitumor function and immunotherapy efficacy in esophageal squamous cell carcinoma through calcium signaling

Introduction: Macrophages, as a major immune cell population within the tumor microenvironment (TME), play a pivotal role in disease progression and therapeutic outcomes. This study aimed to identify key macrophage subsets associated with ESCC immunotherapy response. Methods: macrophages in ESCC patients was assessed by immunofluorescence staining. RNA sequencing was utilized to explore the role of CXCL2 in modulating macrophage functional phenotypes. The impact of CXCL2 on ESCC immunotherapy was validated by ESCC mouse model. Results: macrophages was correlated with poor survival. Mechanistically, CXCL2 promoted the phenotypic transition of macrophages to an immune-activated state by facilitating cytosolic Ca2+ influx. Additionally, CXCL2 suppressed tumor growth and enhanced the efficacy of anti-PD-1 antibody therapy in ESCC mouse models. Conclusion: Macrophage-specific CXCL2 represents a novel biomarker for predicting immunotherapy efficacy and may potentiate the efficacy of anti-PD-1 therapy in ESCC patients.