Blocking Cholesterol Metabolism with Tumor-Penetrable Nanovesicles to Improve Photodynamic Cancer Immunotherapy

Photodynamic therapy (PDT)-mediated cancer immunotherapy is attenuated due to the dysfunction of T cells in immunosuppressive tumor microenvironment (TME). Cholesterol metabolism plays a vital role in T cell signaling and effector. While the metabolic fitness of tumor infiltrating CD8+ T cells is impaired by nutrition restriction in TME and accumulated metabolites by tumor cells. Here a matrix metalloproteinase-2-sensitive tumor-penetrable nanovesicle is designed to regulate cholesterol metabolism pathway for enhancing photodynamic cancer immunotherapy. The nanovesicles accumulate in tumor and release internalizing RGD to promote deep penetration. Released avasimibe from the nanovesicles simultaneously blocks cholesterol metabolism in CD8+ T and tumor cells, thus reinvigorating the functions of T cells and suppressing the migration of tumor cells. Immune responses induced by PDT-triggered immunogenic cell death are further improved with cholesterol metabolism blockage. Compared with PDT alone, the designed nanovesicles display enhanced tumor growth inhibition in B16-F10 mouse tumor model. The approach provides an alternative strategy to improve photodynamic cancer immunotherapy by cholesterol metabolism intervention.

 

Comments：

Photodynamic therapy (PDT) is a promising cancer treatment strategy that uses photosensitizers to generate reactive oxygen species that can kill tumor cells. However, PDT-mediated cancer immunotherapy is limited by the dysfunctional state of T cells in the immunosuppressive tumor microenvironment (TME). One of the factors that contribute to T cell dysfunction in the TME is impaired cholesterol metabolism.

To address this issue, a team of researchers has designed a matrix metalloproteinase-2-sensitive tumor-penetrable nanovesicle that can regulate the cholesterol metabolism pathway to enhance PDT-mediated cancer immunotherapy. These nanovesicles are designed to accumulate in the tumor and release internalizing RGD to promote deep penetration. The nanovesicles also release avasimibe, which is a cholesterol metabolism blocker that simultaneously reinvigorates the functions of CD8+ T cells and suppresses the migration of tumor cells.

The approach is effective in enhancing the immune responses induced by PDT-triggered immunogenic cell death, and the nanovesicles display enhanced tumor growth inhibition in a B16-F10 mouse tumor model compared with PDT alone. Overall, the designed nanovesicles provide an alternative strategy for improving PDT-mediated cancer immunotherapy by intervening in cholesterol metabolism.

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