Cytokine release syndrome in solid tumours: mechanism-based therapeutic strategies for prevention and management

Cytokine release syndrome (CRS) represents a spectrum of immune hyperactivation initiated by rapid T-cell engagement and amplified through innate immune cells, particularly monocytes and macrophages, with downstream cytokine cascades driving endothelial dysfunction, capillary leak and organ impairment. CRS is a frequent, class-associated toxicity of T-cell-engaging immunotherapies and is being observed with increasing regularity as T-cell-redirecting therapies progress through clinical development in solid tumours. Although CRS is typically less severe in patients with solid tumours relative to those with haematological malignancies, phase II-III trials of these emerging agents consistently report grade 1-2 CRS in the majority of patients, highlighting the need for effective prevention and management strategies, while preserving anti-tumour activity of the primary therapy. Current grading and management algorithms have been largely extrapolated from experience with chimeric antigen receptor T-cell therapies and rely on step-up dosing, premedication, supportive care and escalation to interleukin (IL)-6/IL-6R blockade and corticosteroids. However, steroid-refractory or high-grade CRS, as well as overlapping syndromes underscore the limitations of this approach and the need for mechanism-based interventions targeting upstream mediators and signalling hubs. These include IL-1 blockade, Janus kinase-signal transducer and activator of transcription inhibition, granulocyte-macrophage colony-stimulating factor neutralisation, tumour necrosis factor-alpha inhibition and interferon gamma blockade. In this narrative review, we synthesise the mechanistic rationale and emerging clinical evidence underpinning CRS prevention and management in solid tumours, with a particular focus on T-cell engager (TCE) and other T-cell-redirecting therapies. We then outline key risk-mitigation strategies and discuss their potential implications for anti-tumour immunity. Finally, we highlight key knowledge gaps, particularly the paucity of prospective solid tumour-specific data, with current CRS prevention and management strategies therefore remaining largely extrapolated from haematological malignancies, alongside the need for biomarker-driven risk stratification, optimal sequencing and prophylactic strategies and the development of next-generation TCE designs.