CAF-macrophage crosstalk fuels immunotherapy resistance

Abstract

Gastric cancer peritoneal metastasis (GCPM) remains a formidable clinical challenge, characterised by poor prognosis and limited therapeutic options. Despite the transformative impact of immune checkpoint blockade (ICB) therapy across various cancer types, its efficacy in GCPM remains restricted, primarily due to profoundly immunosuppressive mechanisms within the tumour microenvironment (TME).1 2 Li et al recently conducted a single-cell transcriptomic analysis of tumour samples from a phase II trial evaluating ICB (sintilimab) combined with chemotherapy in patients with GCPM.2 Their study established a comprehensive single-cell transcriptional atlas, revealing a novel mechanism driving ICB resistance.2 They identified a unique stroma–myeloid niche dominated by THBS2+ matrix cancer-associated fibroblasts (mCAFs) and SPP1+ tumour-associated macrophages (TAMs), within resistant tumours, forming an immunosuppressive hub mediated via complement signalling.2 Specifically, THBS2+ mCAFs secreted complement component C3, engaging its receptor, C3aR (encoded by C3AR1 ) on macrophages. This C3–C3aR signalling drove the recruitment of peritoneal cavity-resident macrophages and their differentiation into SPP1+ TAMs within the tumour niche.2 These infiltrating SPP1+ TAMs correlated with local T cell dysfunction and low natural killer (NK) cell infiltration. Notably, disrupting the CAF-TAM axis in vivo using a C3aR antagonist (SB290157) increased CD8+ T cell infiltration and significantly enhanced anti-programmed cell death protein-1 (PD-1) responses compared with anti-PD-1 alone.2 These findings provide proof of concept that targeting the complement-driven CAF-macrophage crosstalk can remodel the TME and overcome ICB resistance. The insights from Li et al align with the broader understanding that successful immunotherapy often hinges on the state of the TME, with CAFs and TAMs as principal architects of immunosuppressive or immune-excluded environments. Beyond gastric cancer, numerous studies have …