Combinatorial in situ cancer vaccines elicit broad, enhanced antitumor responses by leveraging tumor antigens and immune mechanisms.

Cancer immunotherapy faces significant hurdles, as conventional tumor-associated antigen (TAA) or personalized neoantigen vaccines often require predefined targets and complex manufacturing. This limitation, coupled with tumor heterogeneity, can lead to immune escape and inconsistent therapeutic outcomes. The current standard of care struggles with suboptimal intratumoral retention of therapeutics and barriers to T-cell infiltration. In situ cancer vaccination addresses these gaps by leveraging the tumor's full antigenic repertoire—including TAAs, neoantigens, post-translationally modified epitopes, and cryptic peptides—to elicit robust polyclonal cytotoxic T-cell responses and facilitate epitope spreading within the native tumor context.

This conceptual review synthesizes advancements in combinatorial in situ cancer vaccination strategies, focusing on transforming the tumor microenvironment into an endogenous vaccine platform. The approach involves coordinated activation of multiple immune mechanisms, including programmed cell death pathways like immunogenic apoptosis, pyroptosis, necroptosis, and ferroptosis. It highlights the incorporation of potent adjuvants and advanced delivery platforms, such as nanomedicine-enabled systems, to enhance innate-adaptive crosstalk. The review also emphasizes combinatorial strategies, particularly with immune checkpoint blockade, to overcome challenges like inconsistent immunogenic cell death induction and suboptimal intratumoral retention.