This review synthesizes the mechanistic insights, engineering strategies, clinical evidence, and emerging platforms, including in vivo lentiviral CAR-T generation, that define the current landscape, and proposes a tiered framework for next-generation solid tumor CAR-T development, while explicitly acknowledging the limitations and unknowns that persist.
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy has produced remarkable therapeutic results in blood cancers, while its application to solid malignancies remains limited by a pooled objective response rate of approximately 9%. This gap stems from core biological obstacles: heterogeneous antigen expression, physical inaccessibility within dense stromal architectures, and immunosuppressive microenvironments that drive T-cell exhaustion through epigenetically fixed transcriptional programs. The period spanning 2024–2025 represents a pivotal turning point. GD2-targeting CAR-T cells delivered intracerebroventricularly achieved durable complete responses (including one sustained beyond 30 months) in H3K27M-mutated diffuse midline gliomas. CLDN18.2-targeting satricabtagene autoleucel demonstrated randomized superiority over physician’s choice in advanced gastric cancer (progression-free survival HR 0.37). GPC3-targeting CAR-T cells armored with a dominant-negative TGF-β receptor achieved objective response rates of 50–57% in hepatocellular carcinoma, representing a three- to four-fold improvement over unarmored predecessors. These breakthroughs reflect a paradigm shift from potency-driven engineering toward resilience-based design: metabolic armoring via autocrine IL-10 and IL-15, epigenetic protection through DNMT3A disruption and c-Jun overexpression, logic-gated targeting via synNotch circuits, and microenvironmental shielding through dominant-negative receptors. Beyond the local microenvironment, emerging recognition of systemic neuroendocrine-immune dysregulation further informs CAR-T persistence and fitness considerations. This review synthesizes the mechanistic insights, engineering strategies, clinical evidence, and emerging platforms, including in vivo lentiviral CAR-T generation, that define the current landscape, and proposes a tiered framework for next-generation solid tumor CAR-T development, while explicitly acknowledging the limitations and unknowns that persist.
Glioblastoma (GBM) is the most lethal primary brain tumor, with a median survival of 15 months despite intensive treatment. Chimeric antigen receptor (CAR) T-cell therapy, while transformative in hematological malignancies, consistently fails in GBM because the immunosuppressive tumor microenvironment (TME) drives T-cell exhaustion. We examined transcriptional programs, microenvironmental factors, and metabolic competition that collectively drive exhaustion in this context. Then we reviewed 5 convergent engineering strategies: localized cytokine delivery to bypass autocrine deficits; adjunctive antibody therapies to remodel the TME; oncolytic viruses armed with chemoattractants or cytokines as immunomodulators; coexpression of cytokine or chemokine receptors to provide survival signals; and multiplexed CRISPR-Cas9 editing to disrupt exhaustion checkpoints and enable site-specific CAR integration. Locoregional delivery consistently outperforms systemic administration, demonstrating that physical barriers are as critical as cellular engineering. Despite this progress, antigen heterogeneity, metabolic limitations, and the need for combinatorial targeting remain the principal unresolved challenges. An overview of the key concepts discussed in this review is presented in the graphical abstract.
Ali Anvarian, Fatemeh S. M. Nazari, Ali Karimi Jashni· Journal of immunotherapy· 0 citations
The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.
Wei Cheng, Mei-Lan Liu, Yu-Hua Diao et al.· Cancer Biome and Targeted Th...· 0 citations
Next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.
Zi-Yan Kong, Jin-Ke Wang· Frontiers in Immunology· 0 citations
Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.
Lin Chen, Z. Zou· Critical reviews in oncology...· 0 citations
Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers due to its aggressive biology and resistance to existing therapies. Oncofetal chondroitin sulfate (ofCS) is a tumour-restricted glycosaminoglycan broadly expressed across solid cancers but largely absent from normal adult tissues. We developed C9-based chimeric antigen receptor (CAR)-T cells targeting ofCS to overcome poor antigen specificity and the immunosuppressive tumour microenvironment (TME). Objective To optimise ofCS-targeted C9 CAR-T cell therapy for PDAC through integrated CAR design optimisation, metabolic enhancement and TME reprogramming. Design C9 and charge-optimised C9-66 CAR-T cells were engineered using a humanised ofCS-binding single-chain antibody fragment. Antitumour efficacy, functional durability and metabolic fitness were assessed in murine and patient-derived PDAC models. Enhancement strategies included inosine-mediated metabolic reprogramming, Nr5a2 overexpression and sequential TME remodelling using GLP-1R modulation, CSF-1R blockade and programmed cell death protein-1 inhibition. Results C9 CAR-T cells exhibited potent cytotoxicity, delayed tumour progression and extended survival in PDAC models. Compared with the parental construct, charge-optimised C9-66 CAR-T cells showed reduced exhaustion and more sustained activity in vivo. Inosine enhanced cytokine production, promoted central-memory differentiation and mitigated exhaustion, whereas Nr5a2 overexpression increased mitochondrial respiration and cytotoxicity. Sequential GLP-1R on–off modulation with macrophage and checkpoint blockade enhanced intratumoural CAR-T cell activity and prolonged survival. Human C9-66 CAR-T cells retained specific ofCS recognition and lysed patient-derived PDAC cells in vitro and in vivo. Conclusion C9-66 CAR-T cells with metabolic optimisation and TME reprogramming represent a tumour-specific and clinically translatable immunotherapeutic strategy for PDAC and other ofCS-expressing solid tumours.
Ke Jiang, Chu-Hu Lai, Shuang Dong et al.· Gut· 0 citations
