In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy. However, systemic administration of immunostimulatory agents or chemotherapeutics often results in toxicity and immune-related adverse events. Herein, we developed a tumor microenvironment (TME)-responsive nanoprodrug by conjugating the Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) with the chemotherapeutic agent doxorubicin (DOX) via a matrix metalloproteinase-9 (MMP-9)-cleavable peptide and polyethylene glycol (PEG), forming an amphiphilic conjugate that spontaneously self-assembled into stable, injectable nanoparticles (named as MPPD NPs). Upon reaching the TME, MMP-9-mediated cleavage of the peptide linker triggered the disintegration of the nanoparticle outer structure, resulting in localized DOX release. The released DOX induced immunogenic cell death of tumor cells, promoting the release of damage-associated molecular patterns and initiating immune responses. Simultaneously, the residual MPLA-PEG core nanoparticles (MP NPs) were internalized by dendritic cells, triggering the TLR4 signaling pathway to enhance tumor antigen presentation and cytokines secretion, thereby eliciting robust CD8+ T cell-mediated cytotoxic immune response. In vivo, this nanoprodrug not only effectively suppressed tumor progression and extended survival time in tumor-bearing mice but also significantly reduced DOX-associated cardiotoxicity. RNA sequencing of tumor tissue further confirmed that MPPD NPs potentiate ISV by activating immune-related pathways. This study presented a safe and effective ISV strategy that elicits robust tumor-specific immunity and provides a new insight into the design of combinatorial chemo-immunotherapeutic nanoplatform.
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