Cholesterol Metabolism Regulated Nanoliposome Ameliorates Chemo/Photothermal Therapy Reversing CD8⁺ T Cell Exhaustion

Abstract

Stimulating the immunogenic cell death (ICD) by chemical and photothermal agents triggers antitumor immune responses to tumor treatments. However, the abnormal cholesterol accumulation in cancer cells promotes tumor survival and metastasis, while the high concentration of cholesterol in the tumor microenvironment will result in T exhaustion. Herein, a cholesterol-regulable nanoliposome (ictLipo) that encapsulated with IR806, tirapazamine, and cholesterol oxidase (ChOx) was fabricated to boost chemo/photothermal-activated ICD and antitumor immune responses. Specifically, the released ChOx oxidizes cholesterol, accompanied by oxygen consumption and ATP reduction. Whereupon, tumoral anabatic hypoxia activates the toxicity of tirapazamine while ATP reduction strengthens photothermal therapy of the IR806 by suppression of HSP70. We found that this interactive strategy evokes robust ICD and reverses T-cell exhaustion. When combined with the immune checkpoint blockade, ictLipo can efficiently restrain breast cancer metastasis in two tumor models. The interactive strategy sheds new light on the immunological facet of cholesterol metabolism and may provide a new therapeutic strategy against breast cancer.

Keywords

checkpoint blockade / cholesterol metabolism / photothermal therapy / T cell exhaustion

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2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.