The insider's perspective: The intracellular complosome and immune cell dynamics in cancer

Complement is increasingly recognised as a driver and modulator of antitumour immunity, with context-dependent effects across T cells, myeloid subsets, stromal elements and tumour cells. Although best known for pathogen clearance and membrane attack complex (MAC) formation, complement also acts intracellularly via the 'complosome' to regulate cellular homeostasis and gene expression. Complosome activity may dampen antitumour responses by rewiring single-cell metabolism and transcription, altering nutrient flux and fostering an immunosuppressive microenvironment. Here, we synthesise advances in intracellular and extracellular complement, with emphasis on complement component 3 (C3) and receptors (C3aR1, C5aR1/CD88, C5aR2/C5L2), highlighting how these pathways shape T-cell metabolism, exhaustion programmes and inflammatory tone within tumours. Evidence indicates that tonic C3/C5 signalling restrains cytotoxicity via C5aR1-driven myeloid recruitment and cytokine cascades, while complosome signalling tunes T-cell activation thresholds and bioenergetics. We outline considerations for selectively modulating intracellular versus extracellular complement, propose cell-type-resolved biomarker strategies and identify opportunities for complosome-directed therapies in cancer, integrating roles across T cells, macrophages, B cells, neutrophils, NK cells, regulatory T cells, dendritic cells, myeloid-derived suppressor cells and cancer-associated fibroblasts. KEY POINTS: Intracellular complement (complosome) shapes the tumor immune microenvironment. Complosome's role in cancer is underrecognized yet central to tumor immunity. C3/C5-driven complosome signals rewire T cell activation, fate, and metabolism. Complosome activity can promote pro-tumor immune cell function. Blocking the complosome, alone or with checkpoint inhibitors, unveils a new tumor target.