CAR-T cell immunotherapy is an adoptive cell therapy that involves the genetic modification of a patient's T lymphocytes, followed by in vitro expansion and reinfusion to enhance antitumor immunity. A conventional CAR construct consists of extracellular, transmembrane, and intracellular domains. The extracellular domain typically comprises a single-chain variable fragment (scFv) derived from the variable regions of antibody light and heavy chains, allowing specific tumor-associated antigen (TAA) recognition independent of major histocompatibility complex (MHC) molecules. The intracellular signaling domain, responsible for T cell activation, generally includes co-stimulatory signaling motifs and a CD3ζ domain. This MHC-independent antigen recognition enhances the specificity and cytotoxicity of CAR-T cells against tumor cells [1]. Currently, CAR-T cell therapy has been approved for the treatment of various hematologic malignancies and is being actively explored for its potential application in solid tumors [[2], [3], [4], [5], [6]].

Although CD19 CAR T-cell therapy has achieved impressive complete response (CR) rates—ranging from 60 to 93 % in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and 40–58 % in B-cell non-Hodgkin lymphoma (B-NHL)—its long-term efficacy remains a challenge. Approximately 40 % of B-ALL patients experience relapse, while only 30–40 % of B-NHL patients achieve sustained remission [[7], [8], [9], [10], [11], [12]]. Similarly, despite high CR rates and overall response rates (ORR) exceeding 70 % in clinical trials for relapsed/refractory multiple myeloma (RRMM), the durability of response with the two commercially approved BCMA-targeted CAR T-cell therapies remains limited, with a significant proportion of patients eventually relapsing [[13], [14], [15], [16], [17]]. The mechanisms underlying resistance to CAR T-cell therapy primarily involve: (1) antigen escape mediated by downregulation or loss of target antigens on tumor cells [9,18]; (2) T-cell exhaustion, characterized by progressive functional impairment and limited persistence of CAR-T cells [[19], [20], [21], [22]]; and (3) immune checkpoint adaptation, where upregulation of inhibitory receptors (e.g., PD-1, LAG-3) within the immunosuppressive TME suppresses CAR T-cell cytotoxicity and impairs antitumor efficacy [[23], [24], [25]].

PD-L1, a widely expressed negative regulatory molecule on tumor cells, plays a crucial role in suppressing immune cell activity within the TME. It not only impairs the antitumor functions of adoptively transferred immune effector cells but also promotes the generation of Foxp3+ regulatory T cells (Tregs) in the TME. These mechanisms contribute to T cell dysfunction by inducing anergy, exhaustion, and apoptosis [26]. Currently, multiple PD-1 and PD-L1 antibodies have been approved for cancer immunotherapy [27]. In addition, various design strategies targeting the PD-1/PD-L1 axis have been explored in CAR-T cell therapy. Yuti and colleagues engineered BCMA-CAR-T cells co-expressing an anti-PD-L1 scFv to block the PD-1/PD-L1 axis, which boosting T cell proliferation, alleviating exhaustion, and restoring antitumor function [28]. CRISPR/Cas9-mediated PD-1 knockout boosted anti-CD19 CAR T cell efficacy, enhancing tumor killing in vitro and PD-L1+ xenograft eradication in vivo [29]. Xiangke Xin and colleagues demonstrate that PD1 inhibitor maintenance following CD19/22 CAR-T cell therapy not only obtained superior response and survival but also increased the persistence time of CAR-T [30]. In addition, The PD-1/CD28 CSR enhances T cell functionality by integrating the extracellular domain of PD-1 with the transmembrane and intracellular co-stimulatory domains of CD28, which converting PD-L1-mediated inhibitory signals into CD28-driven T cell activation and effectively reprogramming the immunosuppressive TME [31].

The interleukin-7 receptor (IL-7R) is a heterodimer composed of the IL-7Rα (CD127) chain and the common γ-chain (CD132), which is shared by several cytokine receptors. Upon binding to IL-7, the receptor activates multiple downstream signaling pathways, including the JAK1/JAK3–STAT5 axis, PI3K–AKT, and MEK–ERK pathways. These cascades promote T cell survival, homeostatic proliferation, and memory differentiation [[32], [33], [34]]. Here, we engineered CD19/BCMA-directed CAR T cells co-expressing a PD1IL7R CSR to reprogram PD-L1-mediated immunosuppression in the TME. Unlike PD1/CD28 CSR, which convert PD-L1–mediated inhibition into CD28-derived costimulatory signals that enhance early CAR-T cell activation and effector function, the PD1/IL7R CSR reprograms inhibitory signaling into IL-7R–dependent pro-survival and proliferative pathways upon engagement with PD-L1+ tumor cells. This mechanism helps rescue CAR-T cell dysfunction in immunosuppressive tumor niches and supports improved persistence and memory formation. This tumor-localized signal conversion specifically enhances CAR T cell expansion and persistence while minimizing systemic toxicity, as co-stimulation is strictly dependent on immune synapse formation with PD-L1+ targets [35]. This novel CSR provides a versatile signal-switching platform for improving CAR T cell therapy against both hematologic and solid tumors.