CD40 and cancer: Using three orthotopic mouse models of poorly T cell-infiltrated tumors (AT-3, B16, and 4T1), we evaluated the efficacy of the combinatorial therapeutic regimen, ISIM comprised of intratumoral sequential administration of Flt3L (to recruit cDC1s to the TME), RT (to induce immunogenic death of cancer cells and maturation of DCs), and TLR3/CD40 agonists (to stimulate antigen-loaded cDC1s for priming and expansion of tumor-specific CD8+ T cells) (Fig. 1a).