Association between cholesterol and liver injury risk in solid cancer patients treated with PD-1 inhibitors: evidence from two cohort studies.

BACKGROUND: To assess the association between baseline serum lipids and the risk of severe hepatic immune-related adverse events (irAEs) in solid cancer patients treated with PD-1 inhibitors. METHODS: This retrospective study included a discovery cohort (N = 601) and an independent high-risk population validation cohort (N = 331), all of whom received PD-1 inhibitor therapy at Zhongshan Hospital between 2019 and 2023. Baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured prior to treatment. Hepatic irAEs were systematically evaluated using the CTCAE and RUCAM scores, with grade ≥ 3 (G3+) defined as severe. Restricted cubic spline models and multivariable Cox regression analyses were used to evaluate the associations between baseline lipid levels and the risk of hepatic irAEs. RESULTS: In the discovery cohort, nonlinear associations were observed between baseline TC and LDL-C levels and the risk of G3+ hepatic irAEs (P-value TC=0.021, P-value LDL−C=0.034). Compared with the reference group (LDL-C: 2.47–3.37 mmol/L), patients with elevated LDL-C levels (≥ 3.37 mmol/L) had a significantly increased risk of severe hepatic irAEs (HR = 2.16, 95% CI: 1.13–4.10, P-value = 0.019). Similar associations of elevated LDL-C levels (≥ 3.37 mmol/L) were validated in the high-risk population (HR = 2.09, 95% CI: 1.01–7.73). No significant associations were found between HDL-C or TG levels and the risk of hepatic irAEs. Sensitivity analyses demonstrated consistent results, which were confirmed in the validation cohort. CONCLUSIONS: Elevated baseline LDL-C levels were associated with an increased risk of severe hepatic irAEs in solid cancer patients receiving PD-1 inhibitor therapy. This finding highlights the importance of pre-treatment lipid risk stratification and monitoring in immunotherapy patients.