Baseline circulating immunophenotype as a predictor of immune-related adverse events in NSCLC patients treated with immune checkpoint inhibitors

Background Immune-related adverse events (irAEs) represent a challenge in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (IO). Baseline circulating immunophenotype may identify patients at increased irAEs risk.Methods This observational study included patients with advanced NSCLC receiving IO alone or with chemotherapy. Baseline clinicopathological data and blood samples were prospectively analyzed to investigate the association of clinicopathological characteristics, circulating immune cells and cytokines, with irAEs onset, severity, timing, and type.Results 178 patients were included; 52.2% (n = 93) developed irAEs, more frequently involving those with good ECOG PS, first-line treatment, favorable LIPI, higher albumin. These patients showed higher baseline lymphomonocytes and lower CD4+CD25+Foxp3+ T cells (p = 0.05 and 0.04, respectively). Logistic regression confirmed lymphocyte enrichment as independently associated and Tregs as protective (p = 0.05 for both). High-grade and early-onset irAEs were associated with increased PD-1+ T and NK cells, cytotoxic/proliferative T-cell markers, and reduced inhibitory signals (i.e. sPD-L1). Distinctive immune profiles outlined gastrointestinal and cutaneous toxicities.Conclusions Baseline circulating immunophenotype showed exploratory association with irAE risk, severity, timing, and pattern in this setting. No association retained statistical significance after false discovery rate (FDR) adjustment. These findings should be considered hypothesis-generating and require independent external validation.