Complement system in cancer: friend or foe of immunotherapy

The complement system, a key component of the immune response, plays a dual role in cancer, influencing both tumor suppression and progression. Its three activation pathways (classical, alternative, and lectin) initiate immune processes, including opsonization and cell lysis. Within the tumor microenvironment, however, complement activation can paradoxically support immune-mediated tumor control or contribute to immune evasion and tumor growth. Therapeutic interventions such as radiation and certain chemotherapies can trigger complement activation by inducing immunogenic cell death and the release of damage-associated molecular patterns. This activation leads to the generation of anaphylatoxins C3a and C5a, which recruit immune cells to the tumor site and promote antitumor immunity. However, these same fragments may also foster an immunosuppressive microenvironment by attracting regulatory T cells and myeloid-derived suppressor cells, thereby limiting the efficacy of immunotherapies. Additionally, tumor cells often upregulate membrane complement regulatory proteins, including CD46, CD55, and CD59, to escape complement-mediated cytotoxicity and immune surveillance. Recent insights indicate that the complement system is a critical barrier to effective immunotherapy. Complement inhibition, particularly by targeting C3a receptor and C5a receptor 1, has been shown to synergize with immune checkpoint inhibitors (eg, anti-programmed cell death protein-1/programmed death-ligand 1), reversing complement-driven immunosuppression and enhancing T cell–mediated tumor rejection. Combining complement blockade with proimmunogenic therapies such as radiation or chemotherapy may further amplify these effects by uncoupling therapy-induced complement activation from its immunosuppressive consequences. Thus, the interplay between complement activation and cancer therapeutics presents a promising avenue for treatment innovations. Strategic modulation of complement, whether through genetic, pharmacologic, or antibody-based approaches, could sensitize tumors to immunotherapy and help overcome resistance mechanisms. Continued investigation into this crosstalk will be essential for designing effective combination strategies that maximize antitumor immunity while minimizing immune escape.