The Complosome: An Emerging Intracellular Complement Network in Cancer Development and Therapy.

The complement system is traditionally recognized as a major effector of innate immunity, essential for pathogen clearance, inflammation and the maintenance of tissue homeostasis. In recent years, however, its role in cancer has been substantially redefined. Beyond its canonical extracellular activity, complement has emerged as a multifaceted regulator of tumor biology, acting not only within the tumor microenvironment but also intracellularly through the recently described intracellular complement system (complosome). While extracellular complement primarily shapes immune responses and the tumor microenvironment, the complosome directly regulates fundamental cellular processes, including metabolism, proliferation, autophagy, stress responses and cell survival. In this review, we discuss current evidence on the canonical and non-canonical roles of complement in cancer. Importantly, complement signaling exhibits a strong context-dependent duality, exerting either tumor-promoting or tumor-restraining effects depending on the tumor type, disease stage, cellular source, and localization. Taken together, the available evidence indicates that the complosome is not merely an extension of classical complement biology, but a distinct and biologically significant signaling network that rewrites our understanding of complement in cancer. Its growing relevance in tumor development and therapy resistance positions it as a promising target for future mechanistic studies and innovative therapeutic interventions.