CAR-T cell therapy has revolutionized the treatment of B-cell malignancies and is now showing initial success in solid tumors. Despite continued progress, many patients treated with CAR therapy fail to respond or develop resistance. This highlights the urgent need to further optimize current treatment options.
Disease progression after CAR therapy may be caused by a variety of factors, which can be categorized as tumor-intrinsic, tumor microenvironmental, or lymphocyte-intrinsic resistance mechanisms. Among these factors, those related to CAR-expressing lymphocytes are of particular interest because they have the potential to be altered during in vitro cell manufacturing. In clinical studies, the in vivo expansion and persistence of CAR-T cells are often associated with superior therapeutic efficacy. Recent clinical data suggest that this applies not only to CAR-T cells, but also to CAR-NK cells. Therefore, improving the survival of CAR-T and CAR-NK cells remains a major goal in the field of cell therapy.
Recently, researchers from Memorial Sloan Kettering Cancer Center published a research paper titled "CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit" in Nature Cancer, a subsidiary of Nature. The study showed that the persistence of CAR-engineered lymphocytes (CAR-T cells, CAR-NK cells) is regulated by the FASL-FAS autoregulatory circuit.
Figure 1. Disabling FAS signaling enhances CAR-T antitumor efficacy in vivo. (Yi F, et al., 2025)
Chimeric antigen receptor (CAR) engineered lymphocytes (e.g., CAR-T cells, CAR-NK cells) have been used to treat B-cell malignancies. However, these cells have limited persistence, limiting the full therapeutic potential of these therapies.
The FAS ligand (FAS-L)/FAS interaction regulates lymphocyte homeostasis. There is still an incomplete understanding of which cells in cancer patients express FAS-L and whether these sources affect CAR persistence.
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In this latest study, the research team constructed a single-cell atlas of multiple cancers to identify cell subsets expressing FASLG (the gene encoding FAS-L). The research team found that FASLG expression was mainly restricted to endogenous T cells, natural killer (NK) cells, and CAR-T cells, while tumor cells and stromal cells had little expression.
To determine whether the survival of CAR-T and CAR-NK cells is regulated by FAS-L, the research team performed competitive fitness assays using lymphocytes carrying a dominant negative effector receptor for FAS (ΔFAS). After transplantation, CAR-T cells and CAR-NK cells expressing ΔFAS were enriched, a phenomenon that was reversed by FASLG knockout. In contrast, FASLG was not required for CAR-mediated tumor killing. In multiple models of female mice, ΔFAS co-expression enhanced the anti-tumor effect.
Overall, this study shows that the persistence of chimeric antigen receptor (CAR) engineered lymphocytes is regulated by the FAS-L/FAS autoregulatory circuit.
Reference
Yi F, et al. CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit. Nature Cancer, 2025: 1-18.