Innovations and emerging trends in adoptive cell therapies for solid tumors: engineering strategies and clinical translation

Cancer remains a formidable challenge in global oncology, with conventional treatments often failing to achieve durable responses in advanced stages. Adoptive cell therapy (ACT), despite its revolutionary success in hematological malignancies, faces critical bottlenecks in solid tumors, including a hostile immunosuppressive tumor microenvironment (TME), restricted cellular trafficking, and the rapid onset of T-cell exhaustion. This review systematically explores the evolution of ACT platforms, ranging from foundational tumor-infiltrating lymphocytes (TILs) to precision-engineered chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-T therapies. We highlight how innovative engineering strategies such as the integration of "armored" CARs, synthetic gene circuits, and CRISPR/Cas9-mediated gene editing have been employed to enhance the persistence and polyfunctionality of effector cells. Beyond T-cell-centric approaches, we examine the emerging landscape of diverse immune effector cells, including CAR-natural killer (NK) cells, and CAR-macrophages (CAR-M), which offer unique advantages in antigen recognition and safety profiles. Furthermore, we detail the synergistic potential of multimodal combination regimens, where ACT is paired with immune checkpoint inhibitors (ICIs), localized radiotherapy, or nanotechnology-based delivery systems to dismantle TME barriers and achieve systemic anti-tumor immunity. By tracing the journey of therapeutic cells from ex vivo expansion to intratumoral infiltration and cytotoxicity, this review illuminates the molecular mechanisms governing therapeutic efficacy. Finally, we discuss the current clinical trial landscape, manufacturing hurdles, and the regulatory pathways essential for transitioning these sophisticated cellular products from bench to bedside.