C5aR1-positive PMN-MDSC-induced angiogenesis limits the efficacy of radiotherapy combined with Anti-PD-1 immunotherapy

Radiotherapy (RT) combined with Anti–PD-1 immunotherapy (RT + Anti-PD-1) offers synergistic potential in the treatment of colorectal cancer (CRC). However, RT + Anti-PD-1 often fails to be effective in some patients with CRC, because a subset of tumors exhibits limited responsiveness through mechanisms that remain poorly understood. Here, we identify the complement receptor C5aR1 as a key mediator of reduced sensitivity to RT + Anti-PD-1 in CRC. Transcriptomic profiling revealed a specific upregulation of C5aR1 in tumors treated by RT + Anti-PD-1, and we found its expression was predominantly observed in infiltrating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Functional inhibition of C5aR1 or depletion of PMN-MDSCs restored tumor sensitivity. Mechanistically, RT + Anti-PD-1 elevated C5aR1 expression, promoting C5aR1⁺ PMN-MDSC recruitment and formation of neutrophil extracellular traps (NETs). NETs activated TLR4/9–Traf6 signaling in tumor cells, leading to K63-linked stabilization of hypoxia-inducible factor 1-alpha(HIF-1α), which induced pro-angiogenic and metabolic reprogramming. Collectively, our findings delineate a C5aR1–NET–HIF-1α signaling axis that underlies the reduced therapeutic sensitivity to RT + Anti-PD-1 therapy and highlight this pathway as a potential therapeutic vulnerability in CRC with suboptimal responses to RT + Anti-PD-1.