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Background Macrophages are myeloid-derived immune cells that play a crucial role in regulating immune responses. In the tumor microenvironment (TME), macrophages are often enriched and display an M2-like phenotype, which supports tumor growth and suppresses the function of cytotoxic T cells, resulting in poor clinical outcomes. Fortunately, M2-like macrophages exhibit significant plasticity and can be reprogrammed to an antitumor phenotype through costimulatory signals such as CD40, a tumor necrosis factor receptor (TNFR) family member. Adoptive cell therapy (ACT) is a promising approach that uses T cells to target and destroy tumors. We hypothesized that engineering ACT T cells to deliver CD40 signaling within the TME would induce macrophage reprogramming and a multicellular antitumor response. We developed membrane-bound fusion proteins called Dual Costimulatory Receptors (DCR) that combine the CD40 ligand (CD40L) ectodomain with a costimulatory endodomain to enhance T cell persistence and function. This approach aims to enhance the phagocytosis of tumor cells, recruit additional antitumor immune cells, amplify antigen-specific T cell response, and create a synergistic immune response in the TME.Methods We developed novel, cleavage-resistant CD40L DCRs to prevent the release of soluble CD40L and promote a targeted immunostimulatory effect. Primary CD8 T cells were engineered to express a mesothelin-specific T cell receptor (TCR) alone or in combination with a CD40L-DCR or full-length CD40L (FL, control). The cytotoxic function of T cells was assessed by luciferase assay with tumor cells at various effector-to-target (E: T) ratios. In a macrophage reprogramming assay, M2-like macrophages were differentiated from peripheral blood monocytes, followed by co-culture with CD40L DCR/TCR-T cells and evaluation by flow cytometry. Furthermore, we determined the therapeutic efficacy of the CD40L DCR ACT in in vivo models of acute myeloid leukemia and pancreatic cancer.Results We confirmed stable expression of CD40L on engineered T cells over time. CD40L DCR/TCR-T cells demonstrated significantly enhanced cytotoxicity against tumor cells compared to TCR-only and CD40L FL/TCR-T cells. Human monocyte-derived M2 macrophages were reprogrammed to a pro-inflammatory phenotype when exposed to CD40 signaling delivered by CD40 FL and DCR-expressing T cells. Our in vivo data demonstrated reprogramming of anti-tumor macrophages, leading to significantly enhanced tumor control and improved survival with CD40L-CD40 DCR/TCR-T cells.Conclusions Our findings provide strong evidence that CD40L DCRs can enhance ACT by reversing myeloid-driven immunosuppression within the TME. This innovative approach holds promise for enhancing the efficacy and safety of immunotherapy and achieving improved outcomes across various cancers.