Impressive results in cancer treatment have been obtained through immunotherapy. However, abnormally high cholesterol metabolism in the tumor microenvironment (TME) leads to poor immunogenicity or even immunosuppression, which dramatically reduces the clinical response of patients with oral squamous cell carcinoma (OSCC) to immunotherapy. In this study, a cholesterol-modulating nanoplatform (PYT NP) is developed to restore the normal immune microenvironment, significantly inhibiting SQLE (an essential gene for cholesterol biosynthesis in tumor cells) by releasing terbinafine, thereby reducing cholesterol in the TME and suppressing tumor cell proliferation. In addition, the nanoplatform is equipped with a second near-infrared (NIR-II) photosensitizer, Y8, which triggers immunogenic cell death of tumor cells, thereby promoting intra-tumor infiltration and immune activation via the production of damage-associated molecular patterns for photoimmunotherapy. PYT NPs show great promise in stimulating strong cholesterol-modulating anticancer immunity combined with photoimmunotherapy, opening up a new avenue for sensitized OSCC immunotherapy.
Keywords: cholesterol metabolism modulation; immunogenic cell death; immunotherapy; nanomedicine; oral squamous cell carcinoma.
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