Mini-review discusses combination regimens built on immune checkpoint inhibitors and their associated immune-related adverse events.

Combination regimens built on immune checkpoint inhibitors (ICIs) can deepen antitumor immunity but also reveal a key translational bottleneck: how to escalate immune pressure while preventing immune-related adverse events (irAEs). IrAEs arising in combination therapy are framed as systems-level tolerance failures, driven by cytokine-network rewiring, myeloid–T cell feedback, antigen spreading, and tissue-resident immune programs that shape organ-specific toxicity phenotypes. Our distinctive contribution is an integrative framework that maps these mechanisms to measurable readouts and clinical decision points. We highlight pragmatic systems-immunology strategies to separate productive antitumor activation from early off-tumor inflammation and enable risk stratification across trials and real-world practice. This mini-review consolidates organ-focused recognition and severity-adapted management principles and discusses toxicity-mitigation approaches designed to preserve anticancer efficacy. We also outline reporting standards to harmonize toxicity phenotyping and endpoints across combination studies. Together, this synthesis connects combination design with deployable monitoring and prevention concepts for safer, more effective immunotherapy.