Cancer‐associated fibroblasts (CAFs) promote cancer stem cell (CSC)‐mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, Gemini‐like homotypic targeting nanoparticles (NPs) are designed for two‐pronged CAF transformation and cancer cell elimination. The CAF‐targeted NPs couple vitamin B3 metabolic reprogramming to epigenetic modulation of secreted pro‐stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first‐line chemotherapeutics, a single dose of hydrogel co‐delivering the Gemini‐like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long‐term protection against tumor rechallenge. This study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance.
Dendritic cells (DCs) are crucial mediators of innate and adaptive antitumor immunity, whereas exogenously and endogenously driven lipid accumulation causes immune tolerance of tumor‐associated DCs (TADCs) and thereby diminishes tumor responsiveness to various therapies. Herein, a type of multilevel lipid rewiring nanoparticles (NPs) for TADC revitalization is designed. These self‐assembled NPs specifically bind to the lipid transport receptor Msr1 on the TADC surface and orchestrate the restriction of extracellular lipid uptake, cytoplasmic de novo lipid biosynthesis and nuclear lipogenic gene transcription. It is found that the slimming of TADCs via the three‐in‐one lipid metabolic reprogramming substantially promotes their maturation and rehabilitate their functions in inflammatory cytokine production, cytotoxic T cell recruitment, and tumor inhibition. Significantly, tumor resistance to immune checkpoint blockade therapy is further overcome. The study presents a non‐canonical strategy to remodel tumor‐infiltrating immune cells and paves a new path for improving the efficacy of cancer immunotherapy.
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