Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.