ANXA1 facilitates myeloid-derived suppressor cell infiltration in the non-small cell lung cancer immunomicroenvironment via the STING/NF-κB/CXCL5/CXCR2 signaling axis to enhance tumor progression

Abstract

The infiltration of immune cells within the tumor microenvironment is a crucial determinant of the therapeutic efficacy of cancer immunotherapy. In non-small cell lung cancer (NSCLC), elucidating the regulatory mechanisms that govern the immune microenvironment is of substantial clinical importance. This study identifies Annexin A1 (ANXA1) as a key mediator in promoting the establishment of an immunosuppressive microenvironment driven by tumor cells. Clinical findings demonstrate that increased ANXA1 expression in NSCLC is highly correlated with worse prognosis and reduced effectiveness of immunotherapy. Complementary in vivo experiments further demonstrate that ANXA1 facilitates subcutaneous tumor progression and enhances the recruitment of myeloid-derived suppressor cells (MDSCs), thus fostering an immunosuppressive tumor microenvironment. Mechanistically, ANXA1 modulates the methylation status of UHRF1 (Ubiquitin-like plant homeodomain and RING finger domain-containing protein 1), disrupting DNA damage repair processes and leading to the accumulation of cytosolic double-stranded DNA (dsDNA), which triggers the activation of the STING/NF-κB/CXCL5 signaling axis. CXCL5 binds to its receptor CXCR2 on MDSCs, thereby promoting their recruitment. Importantly, inhibition of CXCR2 effectively reverses ANXA1-mediated MDSCs infiltration. These results elucidate the essential function of ANXA1 in modulating the recruitment of MDSCs within the immune environment of NSCLC, establishing ANXA1 as a significant therapeutic target for the advancement of innovative immunotherapeutic approaches.