Host determinants of immune-related adverse events during immune checkpoint inhibition

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment of many cancers, but immune-related adverse events (irAEs) have become their principal limitation. This review argues that irAEs are not a random hazard of checkpoint blockade but a largely host-determined outcome layered on a drug-set baseline. The regimen fixes how much toxicity risk exists and, through the checkpoint it blocks, which organs are most likely affected. Within that envelope, host determinants decide which patient crosses the threshold of tolerance, and where. We synthesise the evidence for four classes of host determinant: germline genetic variation, including the IL7 locus and organ-directing human leucocyte antigen (HLA) alleles; the baseline immune landscape; the gut microbiome and metabolic state; and clinical characteristics led by pre-existing autoimmune disease. We draw two distinctions the literature often blurs. First, susceptibility should be read in two stages: determinants measurable before the first dose, which can triage patients, and on-treatment changes, which can only signal an event already emerging. Second, organ-specific toxicity is neither drug- nor host-intrinsic but the product of their intersection, with HLA restriction and shared tumour-tissue antigens offering the clearest mechanistic account of why a particular organ is struck. One theme runs throughout: many host features that raise irAE risk also predict a better antitumour response, so host stratification is a matter of optimising a benefit-to-toxicity balance rather than screening susceptible patients out. Multi-omics and systems immunology are assembling the measurements needed to act on this biology, but no host-based pre-treatment predictor is yet validated for clinical use. Realising one would shift checkpoint immunotherapy from the reactive management of toxicity toward its anticipation.