HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack - PubMed
4 hours ago
- #Cholesterol Synthesis
- #Immune Evasion
- #HMGCS1
- HMGCS1 is identified as a key enzyme for repairing PM damage caused by perforin from cytotoxic lymphocytes.
- HMGCS1 promotes PM repair through de novo cholesterol synthesis, which enhances tumor cell resistance to lymphocyte-mediated killing and reduces the efficacy of various immunotherapies, including NK, CAR-T, and anti-PD-1 treatments.
- Cholesterol binds to CHMP4B, improving its localization to the PM and facilitating repair. Factors like oncogenic activation, cytokines, and hypoxia upregulate HMGCS1 via c-Jun activation.
- In lung cancer patients, higher levels of c-Jun activation, HMGCS1 expression, cholesterol content, and PM CHMP4B correlate with poorer responses to anti-PD-1 immunotherapy.
- Targeting HMGCS1 is proposed as a strategy to enhance the effectiveness of immunotherapies by inhibiting this tumor immune evasion mechanism.