Complement in cancer-associated fibroblasts: sources, regulation and context dependence

Complement genes recur in the transcriptomes of cancer-associated fibroblasts (CAFs) and have been independently reproduced across pancreatic, breast, oesophageal, head-and-neck and uveal melanoma tumours. This review argues that complement is a real, perturbable functional dimension of fibroblasts, but that four questions central to interpreting it in cancer remain unresolved: which cell contributes how much complement protein in intact tissue; whether production is coupled to functional self-protection; whether the proximal and terminal ends of the cascade are differentially regulated; and whether the malignant secretome, rather than generic stress, is what induces the phenotype. Across studies the same recurrent signature is assigned to at least seven different CAF state labels, so equating complement-positive fibroblasts with inflammatory CAFs (iCAFs) is a naming convention rather than a validated attribution. Trajectory and atlas evidence suggest complement may be a feature already present in normal and early fibroblasts that declines with progression; direct induction and perturbation evidence comes mainly from therapeutic injury, chronic inflammation or already-established CAFs; and no study yet pairs a malignant with a matched non-malignant secretome under a multi-component complement readout. The central message is that the next step is not another transcriptomic atlas but one defined experiment paired malignant and non-malignant inputs on the same fibroblasts, complement quantified at the protein and secretion level, and fibroblast-specific perturbation with a tissue complement readout, that would address all four questions at once.