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Background Intratumoral vaccines offer a promising avenue in cancer immunotherapy by harnessing the tumor microenvironment to stimulate immune responses. However, challenges persist in maximizing their effectiveness and addressing immune suppression within tumors.Methods Conventional in situ vaccine (CisVac) and α-CD137 antibody were administered in implanted mouse models of lung and colon cancer to evaluate therapeutic efficacy. The initiation mechanism of CD8 + T cells was determined using antibody blockade and transgenic mouse models. Single-cell RNA sequencing was used to further characterize the activation mechanism of T cells.Results Our findings indicate that this synergistic approach markedly inhibits tumor growth while eliciting a robust antitumor immune response, characterized by heightened activation and cytotoxic differentiation of CD8 + T cells, as well as the polarization of conventional dendritic cells (cDC1). Mechanistically, it promotes the cDC1-dependent proportion and cytokine production of tumor antigen-specific CD8+ T cells, mobilizes and establishes enduring systemic immune memory. Our single-cell transcriptome analyses revealed that the therapy facilitates a functional remodeling of regulatory T cells (Tregs) with upregulated inflammatory genes, potentially attenuating immune suppression. Cell–cell communication analyses highlighted interactions between CD4+ Th1-like/Th17 cells and monocytes/DCs through the CD40L-CD40 pathway, indicating potential intercellular regulatory mechanisms.Conclusions Our results highlight the transformative potential of the CisVac/α-CD137 combination in cancer immunotherapy, paving the way for further exploration of its clinical utility and long-term efficacy.