Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has significantly improved the prognosis of patients with various malignancies. However, the immune-related adverse events (irAEs) and associated organ dysfunction they trigger have become key issues affecting treatment safety and long-term patient survival. Pathophysiologically, irAEs share common features with classical critical illnesses like sepsis, both involving host/organ unregulated response (HOUR). The key distinction lies in irAEs primarily manifesting as overactivation of the immune system. Clinically, differentiating irAEs from infection in ICI-treated patients presenting with new-onset organ dysfunction is often challenging. Building upon the HOUR theoretical framework, this article proposes a PRISM management strategy integrating multi-omics technology, aiming to provide a personalized approach for the diagnosis and treatment of immunotherapy-related organ dysfunction. The PRISM strategy encompasses five key components: Precise etiological differentiation, Regulation of host response, Immunotherapy risk prediction, Support of organ function, and Multidisciplinary collaboration. By integrating multi-omics biomarkers and patient clinical characteristics, the PRISM strategy enables early warning and precise phenotyping of organ dysfunction and offers individualized intervention plans. It holds promise for significantly improving the clinical management of irAEs, enhancing patients' quality of life and long-term prognosis, thereby providing a theoretical foundation and practical guidance for the precise prevention and treatment of critical illnesses associated with immunotherapy.