Inhibitory receptor profiles for joint prediction of benefit and toxicity in immune checkpoint blockade

Immune checkpoint blockade has transformed cancer therapy, but durable benefit is limited to a subset of patients and can be accompanied by immune-related adverse events. This Review evaluates inhibitory receptor profiles as candidate biomarkers for predicting both antitumor benefit and immune toxicity. We examine how receptor abundance, co-expression, cellular lineage, clonality, spatial context, and treatment-induced dynamics shape interpretation across tissue imaging, cytometry, bulk transcriptomics, single-cell multi-omics, and spatial profiling, with particular attention to organ-specific toxicity and time-dependent analytical bias. Current evidence supports context-dependent associations, especially for multi-receptor T-cell states and early on-treatment changes, but not universal thresholds or stand-alone clinical use. Because benefit and toxicity share pathways yet arise from partly distinct biological determinants, they should remain separate model outputs. We propose a staged path from mechanistic discovery to a locked minimal assay, external validation, and prospective evaluation of clinical utility.