image: Core immunopathological mechanisms of irAEs: Dysregulation of immune cells and cytokines.
Credit: Anqi Lin, Keyin Zheng
ICIs, representing a revolutionary breakthrough in cancer immunotherapy, restore T-cell antitumor activity by targeting and blocking inhibitory immune molecules, thereby significantly extending the survival of patients with various solid tumors . Since the approval of the first cytotoxic T-lymphocyte-associated protein 4 (CTLA-4） inhibitor, ipilimumab, for advanced melanoma in 2011, ICIs and their combination regimens have successively become first- or second-line treatment options for various cancers, including melanoma, lung cancer, and renal cancer . Currently, clinically applied ICIs primarily fall into three categories: anti-cytotoxic CTLA-4 antibodies (e.g., ipilimumab), anti-programmed death receptor 1 (PD-1) antibodies (e.g., nivolumab, pembrolizumab), and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g., atezolizumab, durvalumab).
Immune-related adverse events (irAEs) are organ-specific or systemic toxic reactions arising from the overactivation of the immune system during ICI therapy; they fundamentally represent autoimmune-like pathological damage triggered by a disruption of the body's self-tolerance . irAEs exhibit the following key clinical characteristics: (1) Multi-organ involvement: irAEs can affect multiple organ systems, including the skin, endocrine system, gastrointestinal tract, and lungs; while cardiac and neurological systems exhibit relatively lower involvement rates, events affecting these systems are often associated with a high risk of mortality and severe sequelae ; (2) Heterogeneity in onset time: irAEs demonstrate distinct temporal dynamics, emerging as early as a few days after the first administration or exhibiting a delayed onset months after treatment discontinuation, and irAEs affecting different organ systems often occur within specific onset time windows ; (3) ICI regimen-specific toxicity profiles: ICIs targeting different molecules exhibit distinct toxicity profiles; anti-CTLA-4 monotherapy is more prone to induce colitis (10%-30%), rash, and hypophysitis, whereas anti-PD-1/PD-L1 agents are significantly associated with pneumonitis (3%-5%) and thyroid dysfunction (10%-20%), and combination therapy involving CTLA-4 and PD-1/PD-L1 inhibitors markedly increases the risk of severe irAEs (up to 50%-60%) ; (4) Complexity of pathogenesis: The development of irAEs involves the dysregulation of a multi-layered immunoregulatory network, including but not limited to abnormal activation of effector T cells, production of autoreactive antibodies, imbalanced release of pro-inflammatory cytokines, alterations in gut microbiota composition, and synergistic effects among various factors, such as those involving cross-reactivity to common antigens.
While ICIs enhance anti-tumor immune responses by attenuating T-cell inhibitory signals, they can also disrupt host immune homeostasis, leading to the activation of complex immunopathological mechanisms. Current research indicates that T-cell dysfunction (e.g., Treg exhaustion and Teff overactivation), aberrant autoantibody production mediated by B cells, cytokine network dysregulation, and monocyte/macrophage-mediated inflammatory cascades collectively form the core molecular basis of irAEs. These mechanisms are interconnected and ultimately induce organ-specific or systemic immunopathological damage through pathways including cross-antigen recognition, aberrant immune cell migration, and remodeling of the local tissue microenvironment. This section will systematically analyze the key molecular pathways implicated in the development of irAEs and their interconnected networks.
The risk of developing irAEs is dynamically influenced by multiple factors, including host characteristics, treatment regimens, tumor biology, and the patient's genetic background. Clinical evidence indicates that a patient's age, sex, baseline immune status, and gut microbiota dysbiosis can significantly influence the threshold for maintaining immune homeostasis; that characteristics of the treatment regimen (such as drug type and combination strategies) can alter the toxicity spectrum via dose-dependent effects; that tumor mutational burden and the tissue-specific microenvironment can shape organ susceptibility; and that HLA polymorphisms and variations in other immune-related genes can determine an individual's genetic susceptibility to specific toxicities. Furthermore, a history of autoimmune disease or the presence of chronic inflammatory states can further elevate the risk of immune dysregulation. This section will synthesize current risk stratification models, incorporating multiple dimensions, to provide a theoretical framework for clinical prediction and preventive strategies.
IrAEs can involve nearly all organ systems, and their clinical manifestations, severity, and management strategies vary according to the characteristics of the target tissue. Cutaneous and gastrointestinal toxicities are the most frequently observed; cardiovascular and neurological toxicities, although less common, are associated with high mortality rates. Furthermore, rare toxicities affecting hematologic, reproductive, and sensory systems, among others, underscore the broad spectrum and diverse nature of irAEs. This section categorizes irAEs by organ system, detailing the clinical features, grading criteria, and management approaches for each type.
Although the clinical application of ICIs has significantly improved the efficacy of cancer treatment, the irAEs they induce remain a critical challenge necessitating further breakthroughs. Future research needs to advance across multiple dimensions: systematically elucidating the shared molecular mechanisms between irAEs and anti-tumor effects, particularly by revealing differences in T cell activation thresholds and patterns of cross-antigen recognition, to provide a crucial theoretical basis for individualized drug dosage adjustments in clinical practice; developing targeted irAE prediction and monitoring systems based on emerging technologies such as multi-omics, biomarkers, imaging, and gene sequencing; optimizing strategies for preventing and treating irAEs by focusing on microbiome regulation and optimizing combination therapy strategies; establishing a temporal dynamic map of irAEs and anti-tumor immune responses to balance efficacy and safety through strategies such as dose de-escalation and intermittent dosing; and exploring novel drugs based on irAE mechanisms to minimize off-target toxicity and achieve an optimal balance between anti-tumor efficacy and safety. These breakthroughs will drive the establishment of individualized precision therapy paradigms, ultimately achieving the primary goal of immunotherapy: enhancing efficacy while minimizing toxicity.
COI Statement
Peng Luo hold the position of Executive Editors-in-Chief for Med Research. Jian Zhang hold the position of Associate Editors for Med Research. Aimin Jiang hold the position of Editorial Board Members for Med Research.