Tumor-intrinsic SIRPα drives anti-PD-1 resistance in esophageal cancer by coordinating proliferative dominance and T-cell exhaustion: A target for combinatorial immunotherapy

Signal regulatory protein alpha (SIRPα) is a novel immune checkpoint protein. However, the role and mechanism of SIRPα in esophageal cancer (ESCA) remain unclear. This study explores the role of tumor intrinsic SIRPα in ESCA. Twenty-one ESCA samples treated or not with anti-programmed death protein (PD)-1 were collected for scRNA-seq. Overall, 322 ESCA and 161 paracancer samples were collected. SIRPα knockdown was verified in vivo and in vitro using western blot, ChIP-qPCR, dual luciferase reporter gene assays, co-immunoprecipitation, and mass spectrometry. The mechanisms of SIRPα on immune regulation were revealed using co-culture, flow cytometry, and tumor-killing assay. shSIRPα-AAV9 was used in targeted therapy for ESCA combined with pembrolizumab after tumor formation and verified using NCG humanized mice. ESCA cell samples collected after anti-PD-1 treatment and subjected to single-cell sequencing showed a marked decrease in tumor-intrinsic SIRPα expression. High SIRPα expression correlated with poor prognosis and therapeutic outcomes, suggesting that SIRPα may mediate the efficacy of anti-PD-1 immunotherapy. Furthermore, tumor-intrinsic SIRPα expression was directly activated by the YY1 transcription factor. SIRPα may mediate anti-PD-1 treatment resistance through two mechanisms. On one hand, SIRPα regulates the level of caspase through the YY1- SIRPα-PI3K/AKT pathway, inhibiting tumor apoptosis and promoting tumor proliferation, thereby leading to the formation of dominant clones. On the other hand, the presence of SIRPα on tumor cells can inhibit the killing activity of T cells and mediate T cell exhaustion through a CD47-independent pathway, forming an inhibitory immune microenvironment that antagonizes the anti-PD-1 treatment and affects the therapeutic effect. Genetic modulation of tumor-intrinsic SIRPα expression confirmed that low SIRPα levels prevent tumor proliferation and recurrence. Moreover, coadministration of SIRPα-targeted and anti-PD-1 therapies exhibited a significantly greater antitumorigenic effect than individual monotherapies in mice with ESCA. Tumor-intrinsic SIRPα expression correlates with resistance to anti-PD-1 therapy and poor prognosis in ESCA. Mechanistically, SIRPα promotes proliferative dominance via the YY1–SIRPα–PI3K/AKT axis and drives T-cell exhaustion through a CD47-independent pathway. While these findings suggest SIRPα as a potential therapeutic target, their clinical relevance and safety require rigorous evaluation in future human trials.