Local and Cell-intrinsic complement: The new player in cancer progression.

The complement system, a key component of innate immunity, has a paradoxical role in cancer, acting both as a tumor suppressor and a promoter. While traditionally recognized for its extracellular immune functions, recent discoveries highlight non-canonical, intracellular roles in tumor progression. These findings challenge the conventional view that complement activity is confined to the extracellular space and reveal its unexpected influence on tumor proliferation, immune evasion, and metastasis. Tumors exploit local complement activation to create an immunosuppressive microenvironment, often upregulating regulatory proteins to evade complement-mediated cytotoxicity. Complement proteins can also promote tumor growth and therapy resistance through extracellular signaling and intracellular interactions with oncogenic pathways. The emerging concept of an intracellular complement system, or "complosome," further suggests roles in cell metabolism, immune modulation, and stress responses. Despite these insights, key challenges remain in defining cell-specific complement functions and distinguishing autocrine, paracrine, and intracellular signaling. Current studies rely heavily on gene expression data, which do not fully reflect protein activity. Advances in gene editing, single-cell technologies, and intracellular complement inhibitors will be critical for clarifying the complex roles of complement in cancer and identifying new therapeutic strategies.