Abstract
Immune checkpoint inhibitors (ICIs) have transformed modern cancer therapy by restoring antitumor T-cell responses through blockade of immune tolerance pathways such as CTLA-4 and PD-1/PD-L1. However, the same immune activation that underlies their clinical efficacy can also lead to immune-related adverse events (irAEs), a broad spectrum of inflammatory and autoimmune toxicities that may affect virtually any organ system. The incidence and severity of these events vary according to the specific agent, tumor type, and treatment strategy. While irAEs have traditionally been attributed to dysregulated adaptive immunity, emerging evidence highlights a central and previously underappreciated role for innate immune mechanisms. In this review, we integrate the concepts of immunosurveillance and tumor immunoediting to illustrate how innate immunity contributes to both effective antitumor responses and immune-mediated toxicity. We describe how damage-associated signals and tumor microenvironment cues reprogram innate immune populations-including neutrophils, macrophages, dendritic cells, myeloid-derived suppressor cells, and innate lymphoid cells-toward pro-inflammatory or immunosuppressive states that influence therapeutic outcomes and toxicity risk. Finally, emerging biomarkers are highlighted and key knowledge gaps that currently limit the prediction and prevention of irAEs, positioning innate immunity as a critical regulatory axis and a promising target for developing strategies to mitigate toxicity without compromising anticancer efficacy.