Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection

While autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematological malignancies, their widespread clinical application remains constrained by lengthy manufacturing cycles, prohibitive costs, and variable patient-derived cell quality. Consequently, "off-the-shelf" universal allogeneic CAR-T cells have emerged as a highly anticipated alternative. However, the clinical translation of these allogeneic therapies faces formidable immunological bottlenecks, principally driven by bidirectional immune rejection: graft-versus-host disease (GVHD) and host-versus-graft rejection (HVGR). To overcome these barriers, multi-tiered immune evasion and engineering strategies are rapidly evolving. This review systematically delineates the mechanisms underlying bidirectional immune rejection and comprehensively summarizes state-of-the-art mitigation strategies. Specifically, we explore how GVHD can be abrogated through gene editing (e.g., TCR knockout), expression blockade, and pharmacological interventions. Conversely, we examine how HVGR is being effectively suppressed via passive immune cloaking, active immune defense mechanisms, and the synergistic remodeling of the host immune microenvironment. Furthermore, we highlight the development of alternative, inherently hypoimmunogenic cell sources as a fundamental approach to circumventing these immunological barriers. Ultimately, this review aims to provide a comprehensive framework and forward-looking reference for translating universal CAR-T cell therapies from conceptual design to broad clinical reality.