Nanomedicine-enabled in situ vaccination: Advancing a trilogy of immunogenic cell death induction, antigen presentation potentiation, and microenvironment remodeling

In situ cancer vaccination based on immunogenic cell death (ICD) represents a paradigm-shifting strategy in cancer immunotherapy, leveraging the tumor cells itself as an endogenous source of patient-specific antigens and damage-associated molecular patterns (DAMPs). This approach circumvents the need for exogenous antigen identification while minimizing off-target toxicities. Nanomedicine serves as a pivotal enabler in this paradigm by providing sophisticated spatiotemporal control over the critical stages of the antitumor immunity cycle. Specifically, nanodelivery systems are engineered to potentiate immunogenic antigen/DAMP release, including calreticulin (CRT), high-mobility group box 1 (HMGB1), and extracellular ATP, via precisely controlled chemo-, photo-, or radio-therapy. Furthermore, they amplify endogenous antigen processing and T cell priming through co-delivered molecular adjuvants, promote dendritic cell cross-presentation of tumor-derived antigens, and facilitate targeted delivery to lymph nodes. Concurrently, nanosystems remodel the immunosuppressive tumor microenvironment via the modulation of immunosuppressive immune cells, the blockade of immune checkpoints, and the interference with metabolic pathways. This review systematically examines recent advances in nanomedicine development centered on a trilogy of strategies for in situ induction of ICD, enhancement of antigen presentation and T cell activation, and remodeling the tumor immune microenvironment. We further critically analyze the key obstacles hindering clinical translation and offer forward-looking perspectives on future research directions. The integration of ICD inducers with advanced nanoplatforms represents a promising frontier for eliciting robust and systemic antitumor immunity.