Chimeric antigen receptor (CAR) T-cell therapy constitutes a paradigm-shifting advancement for treating refractory malignancies, demonstrating unique therapeutic capabilities beyond conventional cancer treatments, which has brought new hope to many patients with advanced cancer. This cellular immunotherapy has achieved unprecedented success in hematologic cancers, yet its extension to solid tumors confronts fundamental biological constraints. Lifethreatening toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity originate from dysregulated immune activation cascades, while T cell exhaustion—characterized by hierarchical epigenetic reprogramming and progressive metabolic failure—severely undermines long-term therapeutic efficacy. These dual limitations demand innovative bioengineering solutions to augment both safety profiles and functional persistence. The present review analyzes core biological mechanisms restricting CAR-T efficacy and surveys cutting-edge approaches designed to circumvent these barriers through integrated genetic reprogramming, metabolic optimization, and microenvironment-responsive receptor engineering. Subsequent discussion focuses on how such multidisciplinary strategies could potentiate cellular immunotherapy’s applicability across diverse oncological contexts, ultimately transforming cancer management paradigms.