The cytokine storm, a life-threatening systemic inflammatory syndrome, is the primary driver of multiorgan failure in different clinical situations, including severe infections, autoimmune diseases, chimeric antigen receptor (CAR) T cell immunotherapy for cancer, and genetic syndromes. This review focuses primarily on cytokine storms triggered by severe infections such as viral pneumonia and bacterial sepsis, and explores the underlying mechanisms of cytokine storms and potential therapeutic interventions. Cytokine storms are characterized primarily by the excessive release of proinflammatory cytokines, which are triggered by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and PANoptosis, all of which activate immune signaling cascades. Amplification mechanisms involve positive feedback loops and the failure of negative feedback mechanisms, leading to uncontrolled inflammation. Like a pyrrhic victory, the excessive activation of the immune system eliminated invading pathogens but caused catastrophic damage due to multiple organ dysfunction syndrome (MODS), turning the life-saving response into a life-threatening war. Therapeutic strategies, including cytokine antagonists, Janus kinase (JAK) inhibitors, caspase inhibitors, glucocorticoids, and blood purification therapies, aim to interrupt the self-amplifying cycle of inflammation that propagates organ injury, thereby reducing MODS and mortality. Challenges include optimizing the treatment timing and patient stratification. Future research should focus on combination therapies and personalized medicine based on the heterogeneity of infections and sepsis. Advances in multiomics and targeted therapies provide new hope for managing infections and sepsis.

Sepsis remains a leading cause of global mortality and is characterized by a dysregulated host immune response to infection. Early deaths often result from hyperinflammation and organ dysfunction, whereas late-stage mortality is increasingly attributed to sepsis-induced immunosuppression, leading to secondary infections and viral reactivation. Challenges persist in the identification and management of sepsis-induced immunosuppression, including the lack of standardized immune monitoring methods, the absence of reliable immune biomarkers to guide therapy, and the limited success of immunomodulatory therapies in clinical trials. This review comprehensively summarizes the pathophysiology of sepsis-induced immunosuppression, encompassing immune cell apoptosis and exhaustion, the expansion and activation of immunomodulatory cells, metabolic reprogramming, epigenetic alterations, and iatrogenic factors. We also discuss current diagnostic challenges and explore emerging immunomodulatory strategies, such as cytokine therapies, immune checkpoint inhibitors, and metabolic modulators, as potential approaches to restore immune function. Finally, we highlight the importance of immune phenotyping and individualized precision medicine in the future management of sepsis, and integrating multidisciplinary approaches from mechanistic research to targeted therapies holds promise for improving patient outcomes.

Tissue‐resident macrophages (TRMs) are long‐lived immune cells strategically distributed across organs, where their functional plasticity enables both homeostatic maintenance and pathological dysfunction. This review provides a comprehensive analysis of TRM biology in inflammation and cancer. We first delineate the heterogeneity and developmental origins of TRM subsets across organs, highlighting how organ‐specific niche signals create distinct vulnerability patterns. We then dissect macrophage dysfunction during sepsis, tracing their trajectory from protective anti‐infectious immunity through critical tipping points to immunoparalysis. Next, we examine additional inflammatory contexts, including sterile inflammation, autoimmune inflammation, Type 2 inflammation, and metabolic inflammation, each revealing distinct facets of macrophage functional plasticity. In parallel, we examine how the tumor microenvironment chronically co‐opts TRMs, transforming them into tumor‐associated macrophages that promote angiogenesis, suppress antitumor immunity, facilitate metastasis, and support cancer stem cells (CSCs). Then, a systematic cross‐disease comparison reveals shared mechanisms that underlie the opposing functional outputs of macrophages in inflammation and cancer. Finally, we evaluate emerging therapeutic strategies and propose a paradigm shift from functional blockade toward precise recalibration of macrophage function to restore immune balance across both disease categories. Together, this review highlights the therapeutic potential of targeting shared macrophage regulatory nodes to restore immune balance across inflammation and cancer.