Engineered nanocomplex for targeted delivery of Beclin1 peptide enables autophagy-mediated tumor suppression and immune activation

Although autophagy is a central regulator of cellular homeostasis, its potential to reprogram the immunosuppressive tumor microenvironment (TME) remains largely unexplored. Within the TME, the dysregulated deposition of Tenascin-C (TNC) establishes a formidable extracellular matrix (ECM) barrier that constrains immune cell infiltration and promotes tumor progression. While it is known that autophagic flux mediates TNC degradation, leveraging this intracellular pathway to therapeutically dismantle the TNC-mediated barrier remains challenging. Here, we present a spatiotemporally controlled peptide-nanocomplex designed to selectively activate Beclin1-mediated autophagy. The induction of autophagy directly affects cancer cells via autophagy-associated cell death. Concurrently, this enhanced autophagic flux facilitates the targeted clearance of TNC, leading to the remodeling of the pericellular matrix. This reconfiguration deconstructs the physical barriers to immune exclusion, thereby facilitating robust cytotoxic T cell infiltration and enhancing effector cytokine production, while also attenuating mesenchymal traits. Consequently, our strategy significantly suppresses tumor growth and potentiates the efficacy of immune checkpoint blockade. Taken together, this approach translates the mechanistic link between intracellular autophagy and ECM dynamics into a targeted therapeutic strategy, providing a chemical biology platform to reprogram the immunosuppressive tumor niche.