With seven products approved by the US Food and Drug Administration (FDA) for 15 indications and more than 2,600 active clinical trials, chimeric antigen receptor (CAR) T cell therapy is firmly established as an effective therapeutic modality for cancer treatment, and promising early data demonstrate its potential in autoimmune diseases. Key challenges facing the field include extending efficacy to solid tumors and reducing the cost and complexity of manufacturing to improve patient access. In this review, we summarize the clinical lessons learned from the now substantial experience with commercial CAR T cells and clinical trials and discuss three waves shaping next-generation development: multi-engineered and logic-gated CAR T cells, rational combination strategies, and in vivo CAR T cell generation. By integrating clinical experience with emerging strategies, we highlight where CAR T cell therapy has succeeded, where current approaches remain insufficient, and how next-generation cell therapies may be designed to overcome these barriers.
While tertiary lymphoid structures (TLSs) broadly correlate with immunotherapy efficacy, their functional heterogeneity can translate into divergent clinical outcomes. In this issue of Cancer Cell, Hu et al. uncover a microbiota-orchestrated stem-like lymphoid niche in which CD70+ ILC2s sustain progenitor exhausted T cells, and their findings redefine the functional organization underlying TLS-associated antitumor immunity.
In this issue of Cancer Cell, Shi et al. report encouraging early-phase results combining HRS-4642, an allele-specific KRAS G12D inhibitor, with the PD-L1 inhibitor adebrelimab in previously treated metastatic pancreatic cancer. The intravenous combination was safe and well tolerated, notably sparing patients the gastrointestinal toxicity common to oral KRAS inhibitors, and achieved a promising 43% response rate at the recommended dose.
