CD8+ T cell-derived CD40L mediates non-canonical cytotoxicity in CD40-expressing cancer cells

T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas Ligand, and TRAIL, are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase 8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counter-intuitive, non-canonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.