Combinatorial in situ cancer vaccines: unlocking broad and enhanced antitumor responses

Abstract In situ cancer vaccination, also termed intratumoral immunotherapy, transforms the tumor microenvironment into an endogenous vaccine platform by leveraging the tumor itself as a source of antigens. Unlike conventional tumor-associated antigen (TAA) or personalized neoantigen vaccines that require predefined targets and complex manufacturing, in situ cancer vaccination presents the tumor’s full antigenic repertoire, including TAAs, neoantigens, post-translationally modified epitopes, cryptic peptides, and viral antigens within their native context. This broad antigen exposure elicits robust polyclonal cytotoxic T-cell responses, facilitates epitope spreading, and reduces immune escape driven by tumor heterogeneity. The therapeutic efficacy of this approach arises from the coordinated activation of multiple immune mechanisms. Programmed cell death pathways, including immunogenic apoptosis, pyroptosis, necroptosis, and ferroptosis, release tumor antigens and danger-associated molecular patterns (DAMPs) that promote dendritic-cell activation, efficient cross-presentation, and the priming of durable effector and memory T cells. The incorporation of potent adjuvants and advanced delivery platforms enhances innate-adaptive crosstalk and helps remodel the immunosuppressive tumor microenvironment. Despite these advantages, clinical translation is limited by inconsistent induction of immunogenic cell death, suboptimal intratumoral retention of therapeutics, and barriers to T-cell infiltration. Recent advances in nanomedicine-enabled delivery systems, microenvironmental modulation, and combinatorial strategies, particularly with immune checkpoint blockade, are overcoming these challenges. Collectively, these innovations position in situ cancer vaccination as a patient-tailored, broadly applicable immunotherapy capable of eliciting durable and systemic antitumor immunity.