This review examines the transition from single‐axis engineering to an integrated framework that addresses hurdles in sequence, and delineates how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion.
Abstract
Chimeric antigen receptor (CAR) T‐cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T‐cell dysfunction. This review examines the transition from single‐axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion. We also assess strategies that actively reshape the immunosuppressive TME, including depletion of regulatory cell populations, blockade of ‘don't eat me’ signals, and the use of biomaterial scaffolds for locoregional delivery. The synthesis of controllable activation, intrinsic resilience, and extrinsic TME modulation is defining a class of adaptive therapeutic systems. Clinical implementation of this approach requires careful management of toxicities, notably cytokine release syndrome (CRS), and support from advanced monitoring technologies. Progress will depend on rational combinations that move beyond isolated optimisations, enabling cellular therapies to dynamically respond to evolving tumour ecosystems and narrowing the efficacy gap between hematologic and solid cancers.
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
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
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.
Samuel Obiosa Onyekweli, Gloria Osayamen Omoruyi, C. O. Akintayo et al.· Oncoscience· 0 citations
Chimeric antigen receptor (CAR) T-cell therapy has revolutionised cancer gene therapy, yet its expansion into solid tumours is hindered by a critical vulnerability: the autonomous, “always-on” nature of conventional CAR constructs. This unregulated activity drives severe toxicities, including cytokine release syndrome (CRS) and on-target/off-tumour damage, while constitutive signalling in hostile tumour microenvironments (TMEs) accelerates T-cell exhaustion. Early safety strategies relied on irreversible genetic “kill switches,” which sacrifice the therapeutic cell population entirely. This review traces the conceptual evolution of CAR T-cell controllability from binary elimination towards platforms enabling graded, reversible, and spatiotemporally precise regulation. We examine the transition from calibrated signalling architectures and small-molecule-regulated split-CARs to advanced optogenetic and sonogenetic controllers, detailing the biophysics of photoreceptor pairs and their preclinical efficacy. Furthermore, we explore complementary architectures, including autonomous logic-gated receptors. Finally, we propose that the optimal next-generation CAR T product will integrate calibrated signalling, external control, and context-dependent armouring to achieve truly programmable, safe, and durable cellular immunotherapy.
S. Smirnov, Yuriy Zaritskey, Galina Salogub et al.· Frontiers in Immunology· 0 citations
This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments and position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.
Saurabh Upadhyay, Sungwoo Cho, K. Upmanyu et al.· Signal Transduction and Targ...· 0 citations
Developing a mechanistic framework that combines intrinsic T cell reprogramming with adaptation to the tumor context will be crucial for extending durable T cell-mediated immunity to solid cancers.
Hojin Chun, Hyunjin Ju, S. Hwang· BMB Reports· 0 citations
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