PLA1A Inhibition Enhances Chemoimmunotherapy Efficacy by Blocking Immunosuppressive Macrophage Polarization in Colorectal Cancer

Abstract Clinical outcomes are often suboptimal in colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy (NAC). A key determinant of the response to NAC is the functional state of tumor-infiltrating immune cells. Understanding how NAC reshapes the immunological landscape will be essential for refining patient stratification and identifying effective combination treatment strategies. Here, we analyzed paired samples before and after NAC treatment by single-cell RNA sequencing, revealing that NAC treatment significantly reshaped the immune microenvironment. Tumors from NAC non-responders featured increased immunosuppressive M2-like macrophage infiltration, which correlated with elevated phosphatidylserine-specific phospholipase A1 (PLA1A). Mechanistically, PLA1A hydrolyzed phosphatidylserine (PS) exposed by chemotherapy to elevate lysophosphatidylserine (LysoPS), which activated the P2ry10 receptor and downstream signaling to promote M2-like macrophage polarization. Importantly, pharmacological inhibition of PLA1A by cilengitide synergized with chemoimmunotherapy to suppress tumor progression in murine models. Clinically, high plasma PLA1A levels negatively correlated with responses to chemoimmunotherapy. Collectively, these findings reveal a chemotherapy-driven metabolic axis that induces an immunosuppressive milieu by increasing lysoPS release. This axis highlights PLA1A as a therapeutic target to mitigate immunosuppression and improve chemoimmunotherapy efficacy.