Immune Checkpoint Inhibitors in Cancer Therapy: Balancing Anti-tumor Immunity, Autoimmunity, and Immune-related Adverse Events, Volume II

This Research Topic is the second volume of the “Immune-checkpoint Inhibitors in Cancer Therapy” Community Series. Please see Volume I here

Cancer immunotherapy has revolutionized oncology, with immune checkpoint inhibitors (ICIs) becoming integral components of modern anti-cancer treatment strategies. By targeting key inhibitory pathways within the tumor microenvironment (TME), antibodies against CTLA-4, PD-1, and PD-L1 have demonstrated durable clinical responses across multiple malignancies, including melanoma, lung cancer, renal cell carcinoma, hepatocellular carcinoma, and several hematologic cancers. More recently, novel checkpoint molecules such as LAG-3, TIGIT, TIM-3, VISTA, and PVRIG have emerged as promising therapeutic targets, while combinatorial immunotherapeutic approaches are rapidly expanding.

Despite their remarkable clinical efficacy, ICIs may disrupt immune tolerance and trigger a broad spectrum of immune-related adverse events (irAEs) and autoimmune manifestations, thus representing a double-edged sword in cancer therapy. These toxicities may affect virtually every organ system and range from mild and transient manifestations to severe or even life-threatening complications. Endocrinopathies, myocarditis, pneumonitis, inflammatory arthritis, myositis, vasculitis, neurological syndromes, dermatologic disorders, gastrointestinal inflammation, and rheumatic immune-mediated diseases have all been associated with ICI treatment. In parallel, patients with pre-existing autoimmune diseases represent a particularly challenging population due to the risk of disease flare and treatment-related immunotoxicity.

Although awareness of irAEs has substantially increased over the past decade, their true incidence and long-term clinical impact may still be underestimated. Delayed onset toxicities, chronic immune-mediated complications, heterogeneous clinical presentations, and limited long-term follow-up continue to complicate diagnosis and management. Furthermore, the precise cellular and molecular mechanisms driving immune dysregulation remain incompletely understood. Current evidence implicates multiple interconnected pathways, including expansion of autoreactive T-cell clones, impaired regulatory T-cell function, epitope spreading, molecular mimicry, cytokine dysregulation, autoantibody generation, microbiome alterations, and dynamic epigenetic and transcriptional reprogramming. Advances in single-cell technologies, spatial transcriptomics, multi-omics approaches, and artificial intelligence-driven analyses are increasingly contributing to the identification of predictive biomarkers and mechanistic signatures associated with both therapeutic response and immunotoxicity.

At the same time, the growing implementation of combination therapies—including ICIs with chemotherapy, radiotherapy, targeted therapies, CAR-T cells, cancer vaccines, bispecific antibodies, and oncolytic viruses—raises important questions regarding synergistic efficacy and cumulative immune toxicity. Precision approaches for risk stratification, patient monitoring, toxicity prevention, and individualized management are therefore urgently needed.

This Research Topic aims to provide an updated and comprehensive overview of autoimmune manifestations and immune-related adverse effects associated with classical and emerging immune checkpoint-targeting therapies, either as monotherapy or in combinatorial treatment regimens. We welcome contributions addressing, but not limited to:

• Cellular and molecular mechanisms underlying irAEs and autoimmunity

• Predictive, prognostic, and monitoring biomarkers

• Multi-omics, spatial biology, and systems immunology approaches

• Microbiome and metabolic regulation of immunotoxicity

• Clinical management, prevention, rechallenge, and long-term follow-up strategies

• Organ-specific irAEs and chronic immune-mediated complications

• ICIs in patients with pre-existing autoimmune diseases

• Combination immunotherapies and next-generation checkpoint inhibitors

• Translational and precision medicine approaches in cancer immunotherapy

• Real-world evidence and longitudinal patient cohorts

Rheumatologists, oncologists, immunologists, neurologists, endocrinologists, cardiologists, dermatologists, molecular biologists, and computational/translational scientists are invited to contribute Original Research Articles, Reviews, Systematic Reviews, Brief Research Reports, Clinical Trial Articles, and high-quality Case Reports.




Please note: manuscripts based solely on bioinformatics or computational analyses of publicly available datasets without adequate biological, experimental, translational, or independent cohort validation are considered outside the scope of this Research Topic.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Immune checkpoint inhibitors (ICIs), Immune-related adverse events (irAEs), Cancer immunotherapy, Tumor microenvironment (TME), Autoimmunity, Combination immunotherapy, Predictive biomarkers

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.