SR‐B1‐Targeted Cholesterol Depletion Nanosystem Synergizes Cholesterol Metabolic Reprogramming and Immunotherapy for Clear Cell Renal Cell Carcinoma

ABSTRACT Metabolic reprogramming, particularly dysregulated cholesterol homeostasis, represents a critical vulnerability in clear cell renal cell carcinoma (ccRCC). Herein, we identify scavenger receptor class B type 1 (SR‐B1) as a pivotal mediator of exogenous cholesterol uptake in ccRCC, driving intracellular cholesterol overaccumulation that promotes tumor malignancy and immunosuppressive microenvironment formation. We engineered an SR‐B1‐targeted cholesterol depletion nanosystem (CDN), which self‐assembles into supramolecular nanofibers upon ligand binding, thereby disrupting SR‐B1 function and depleting intracellular cholesterol to inhibit malignant progression and reverse immune suppression. Given that metabolic depletion of cholesterol primes the tumor microenvironment for immune activation, we integrated resiquimod (R848), a toll‐like receptor 7/8 agonist, into CDN. This dual strategy synergizes cholesterol metabolic reprogramming with immunotherapy: it starves tumors of critical metabolic substrates (targeting cholesterol intrinsic dependencies) while inducing sustained antitumor immune activation (alleviating extrinsic immunosuppression), culminating in robust antitumor responses superior to monotherapies. Our study establishes SR‐B1 as a therapeutic target linking cholesterol metabolism and immune regulation in ccRCC, demonstrating that receptor‐specific metabolic intervention can synergize with immunotherapy by addressing both tumor intrinsic dependencies and extrinsic immune suppression. This integrated strategy provides a mechanistic framework for developing next‐generation combination therapies in metabolic‐driven cancers.