Background In recent years, chimeric antigen receptor T cell (CAR-T) therapy has emerged as a groundbreaking advancement in oncology, particularly for certain hematologic malignancies. Despite its remarkable therapeutic potential, CAR-T therapy is not without its challenges, as it can trigger a range of side effects such as cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, on-target off-tumor toxicity, graft-versus-host disease, and bone marrow suppression. These adverse reactions have the potential to significantly impede the safety and efficacy of CAR-T treatment. The gut microbiota’s role in immune balance is increasingly recognized, with its modulation emerging as a promising strategy to reduce CAR-T therapy’s adverse effects and enhance patient safety and treatment efficacy.

Methods A comprehensive literature search was conducted across various electronic databases using a set of keywords including ‘Chimeric Antigen Receptor T cell therapy’, ‘side effects’, ‘cytokine release syndrome’, ‘Immune effector cell-related neurotoxicity syndrome’, ‘on-target off-tumor toxicity’, ‘graft-versus-host disease’, ‘bone marrow suppression’, ‘gut microbiota’, ‘probiotics’, ‘prebiotics’, and ‘fecal microbiota transplantation’. This review outlines the progress in leveraging gut microbiota modulation for managing CAR-T cell therapy side effects, describes the influence of gut microbiota on CAR-T efficacy and safety, and discusses the role of dysbiosis in CAR-T-related toxicities. It also summarizes emerging strategies like probiotics, prebiotics, fecal microbiota transplantation, and lifestyle interventions for mitigating CAR-T therapy adverse effects, emphasizing personalized gut microbiota management to enhance treatment outcomes. The synthesis highlights the therapeutic potential of gut microbiota modulation in CAR-T therapy.

Results This review delves into the nexus between gut microbiota and CAR-T therapy’s side effects, examining the potential of probiotics, prebiotics, and fecal microbiota transplantation to modulate the gut microbiota. These strategies aim to attenuate the side effects of CAR-T therapy, thereby enhancing patient outcomes.

Conclusions In conclusion, we outline future research trajectories and the promising clinical implications of harnessing the gut microbiota’s influence on CAR-T therapy. The modulation of gut microbiota presents a novel avenue for improving the safety and efficacy of CAR-T treatment, with the potential to transform oncological care.