Dermatotoxicity of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Current Advances in Mechanistic Insights and Predictive Biomarker Identification.

Abstract

Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). However, the cutaneous immune-related adverse events (cirAEs) they elicit-being the most frequent and earliest-emerging toxicities-not only compromise treatment adherence but also exhibit a distinct positive association with systemic immune activation and antitumor efficacy. Given these characteristics, elucidating the pathogenic mechanisms of cirAEs and identifying predictive biomarkers are critical for the early detection and intervention of cirAEs, as well as for forecasting the onset of other immune-related adverse events (irAEs) and assessing ICI therapeutic prognosis. This review systematically summarizes recent advances in the pathological mechanisms of cirAEs and predictive biomarkers. Mechanistically, cirAEs result from multifactorial interplay, including genetic predisposition, shared antigen-driven cross-reactivity, and breakdown of cutaneous immune tolerance. For predictive biomarkers, strategies span traditional predictors (eg, demographic and immunological features) and their clinical translation challenges to emerging methods leveraging multi-omics integration and radiomics. Finally, this review addresses future challenges and directions in cirAEs research: Specifically, the positive association between cirAEs and efficacy demands accurate differentiation of "manageable toxicities" from "high-risk toxicities"; furthermore, future studies must validate causal biomarkers via prospective multi-omics cohorts and develop AI-driven dynamic prediction models to enable toxicity-stratified management and optimization of personalized immunotherapy.