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.