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

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. 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. 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. 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.