Core Viewpoint - CAR-T cell therapy has shown remarkable clinical efficacy in hematological cancers, but approximately 30%-50% of patients experience disease relapse within one year post-treatment, highlighting the need for improved T cell persistence strategies [2][5]. Group 1: CAR-T Cell Therapy Challenges - Despite the success of CAR-T cell therapy, it is associated with severe toxicities, including cytokine release syndrome and neurotoxicity [2]. - The persistence of T cells is crucial for the efficacy and long-term remission of CAR-T cell therapy, influenced by factors such as the percentage of stem cell-like memory T cells and T cell proliferation capacity [2][5]. Group 2: New Research Developments - A study published by a team from the University of Southern California introduced a novel CAR structure driven by the ZAP327 signaling domain, which significantly reduces cytokine release and T cell exhaustion while generating robust and long-lasting antitumor immunity in mouse models [3][5]. - The ZAP327-driven CAR-T cells demonstrated superior therapeutic antitumor activity compared to traditional CAR-T cells, particularly in low antigen-expressing tumor models, leading to extended survival in mouse experiments [5][8]. Group 3: Mechanisms of Action - The ZAP327 domain modulates TCR signaling, increases the pool of stem cell-like memory T cells, and exhibits metabolic characteristics associated with memory T cells through oxidative phosphorylation pathways [6][8]. - The study emphasizes the potential of ZAP327-driven CAR-T cells to overcome the limitations of current CAR-T therapies and enhance T cell responses against solid tumors [8].