CD40 and cancer: To this end, we employ a combinatorial in situ immunomodulation (ISIM) regimen comprising in situ administration of: (1) Flt3L to mobilize cDC1s to the TME; (2) RT to promote immunogenic death of cancer cells and maturation of DCs; and (3) dual TLR3/CD40 stimulation to activate antigen-loaded cDC1s for priming and expansion of tumor-specific CD8+ T cells.