CIMR-Xin Zhou Published in Acta Biochimica et Biophysica Sinica

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Xin Zhou Published in Acta Biochimica et Biophysica Sinica

Date：2025-11-07

CAR-T Therapy Struggling Against Solid Tumors? Where is the Path to Breakthrough?

CAR-T therapy has achieved remarkable success in hematological malignancies, so why does it seem inadequate against more common solid tumors like lung cancer, liver cancer, and gastric cancer? Has CAR-T's potential been exhausted, or have we simply not found the right key to unlock solid tumors? A team led by Researcher Zhou Xin from Capital Medical University/ Chinese Institutes for Medical Research (CIMR), through an in-depth review, systematically dissects the four major barriers currently facing CAR-T in solid tumors and points the way towards a breakthrough via synthetic biology "intelligent upgrades".

CAR-T (Chimeric Antigen Receptor T cells) therapy is undoubtedly revolutionary in the field of hematological malignancies. However, when the battlefield shifts to solid tumors, which account for over 90% of cancers, its efficacy drops significantly. This is not due to a lack of inherent "talent" in CAR-T, but rather because solid tumors construct far more complex "defensive fortifications" than hematological tumors. Recently, a review published by Researcher Xin Zhou's team from Capital Medical University/ Chinese Institutes for Medical Research in Acta Biochimica et Biophysica Sinica acts like a detailed "military map". It not only clearly marks the multiple obstacles CAR-T encounters on the solid tumor battlefield but also provides a blueprint for creating the next generation of "super CAR-T".

This article will summarize the core insights, focusing on the future directions for CAR-T therapy in tackling solid tumors.

Fighting Alone: CAR-T's "Failure to Acclimatize" in Solid Tumors

CAR-T is like a special forces unit equipped with a "precision guidance system". It can directly recognize specific antigens on the surface of tumor cells through its surface CAR protein, thereby efficiently activating, proliferating, and launching a lethal attack. This mechanism works excellently in dispersed cancer cells of hematological malignancies. However, solid tumors are highly organized, well-defended "fortresses" that make it difficult for CAR-T troops, skilled in "mobile warfare", to advance:

1. The Impenetrable "Wall of Bronze": Solid tumors are encased in dense stromal cells and disorganized blood vessels. CAR-T cells struggle to penetrate this physical barrier and reach the tumor core.

2. The "Poison Gas Battlefield" of the Inhibitory Microenvironment: Even if a few CAR-T cells successfully infiltrate, they find themselves in a "gas chamber"-filled with regulatory T cells, myeloid-derived suppressor cells, and various immunosuppressive factors-which severely suppresses their function, even rendering them "paralyzed".

3. "Cutting Off Supply Lines" through Fierce Metabolic Competition: Tumor cells voraciously consume key nutrients like glucose and amino acids from their surroundings, leaving CAR-T cells "starving", energy-depleted, and losing their combat effectiveness.

4. "Camouflage and Escape" via Antigen Heterogeneity and Loss: Tumor cells are not uniform; some downregulate or completely lose the antigen targeted by CAR-T, causing the CAR-T cells to lose their target, leading to treatment failure and relapse.

Comparison and Insight: CAR-T's Strengths and Weaknesses Compared to TCR-T

To better understand CAR-T's challenges, it's helpful to briefly compare it with another important cell therapy, TCR-T.

CAR-T's advantage lies in its "flexibility and directness": It does not depend on MHC presentation, can directly target cell surface proteins, avoids failure due to tumor MHC downregulation, and its design is relatively universal.

CAR-T's weakness lies in its "simplistic signaling": Its activation signal is overly "straightforward", lacking the sophisticated regulatory mechanisms of the natural T cell receptor. This can lead to tonic signaling, where the cells are in a low-level activated state even without tumor antigen stimulation, resulting in premature exhaustion of CAR-T cells and impacting long-term persistence. Thus, the key to conquering solid tumors is not to abandon CAR-T, but to address its shortcomings through "genetic modification" and "strategic upgrades" to better adapt it to the harsh solid tumor environment.

Core Upgrade: Optimizing the "Power System"-Choice of Costimulatory Domain

The costimulatory domain is the "engine" of the CAR, directly determining the combat effectiveness and endurance of CAR-T cells. Choosing different costimulatory domains is like choosing different power solutions for the troops:

CD28 domain: Strong thrust, suitable for "blitzkrieg". It provides powerful initial activation signals, suitable for situations requiring rapid tumor shrinkage, but may lack endurance and lead to cell exhaustion.

4-1BB domain: Long endurance, suitable for "protracted warfare". It promotes the formation of memory T cells and metabolic fitness, enhancing the persistence of CAR-T cells, which is beneficial for long-term disease control, but the onset of action may be slower.

Emerging costimulatory domains (e.g., ICOS, OX40, HVEM): Specialized functions.

They each have their expertise; for example, ICOS aids in T helper cell regulation, OX40 helps reverse T cell exhaustion, and HVEM can improve metabolic fitness, providing more weapons to address specific challenges. The future design trend is a "tailored" combination choice based on tumor type and treatment goals.

The Path to Breakthrough: Multi-Dimensional Creation of "Super CAR-T"

The review by Xin Zhou's team points out that breaking through the barriers of solid tumors requires a combination of strategies, intelligently upgrading CAR-T from multiple dimensions:

1. Dual-target CAR, adding "double insurance": Simultaneously targeting two tumor-associated antigens can effectively counter tumor antigen escape and significantly reduce the risk of relapse.

2. Metabolic reprogramming, solving the "supply problem": Using genetic engineering to enhance the mitochondrial function of CAR-T cells, enabling them to utilize alternative energy sources and become "self-reliant" in the nutrient-deprived tumor microenvironment.

3. Epigenetic editing, reversing "exhaustion": Using technologies like CRISPR to knock out TET2 or inhibit EZH2 and other epigenetic regulators, fundamentally delaying or reversing the functional exhaustion of CAR-T cells, granting them a longer combat lifespan.

4. Combination therapy: Combined with radiotherapy: Disrupts the tumor stromal barrier and induces immunogenic cell death, paving the way for CAR-T cells. Combined with immune checkpoint inhibitors: Lifts the immunosuppression of the tumor microenvironment, unleashing the fighting capacity of CAR-T cells.

5. Intelligent controllable systems, achieving "precision strikes": Logic-gated CARs: For example, SynNotch CAR, which requires tumor cells to express two specific antigens simultaneously for activation, greatly improving safety and avoiding damage to normal tissues. In addition, remotely and precisely control CAR-T cell activity through external light sources or ultrasound (Light-controlled/Sound-controlled CARs), enabling on-demand activation and stoppage, maximizing control over side effects.

6. Emerging Cell Therapies: CAR-NKT (Chimeric Antigen Receptor Natural Killer T cell therapy) shows significant advantages: It leverages CD1d-dependent immune responses within the tumor microenvironment, achieving excellent anti-tumor activity in vivo. Specifically, CAR-NKT cells can precisely clear CD1d-expressing M2 macrophages and myeloid-derived suppressor cells, dismantling the tumor's immunosuppressive barrier; furthermore, they can promote epitope spreading and activate endogenous T cell immune responses against tumor-associated neoantigens, forming a dual anti-tumor effect of "targeted clearance +immune memory activation".

Future Outlook: The Intelligence and Integration of CAR-T/NKT

The future envisioned by Xin Zhou's team is that CAR-T/NKT will no longer be a single "weapon" but a programmable, controllable, modular "living drug" platform.

AI-driven design: Using artificial intelligence to predict optimal targets and design safer, more efficient CAR structures, significantly shortening the R&D cycle.

Modular integration: Integrating different functional modules into CAR-T/NKT cells, enabling them to kill tumors, remodel the microenvironment, and self-regulate according to the situation.

Researcher Zhou Xin stated: "The challenges for CAR-T/NKT therapy in the field of solid tumors are immense, but the prospects are equally broad. Our current efforts are like equipping the CAR-T/NKT 'special forces' with more advanced equipment, more detailed battlefield maps, and more reliable logistical support. Through the wisdom of bioengineering, we firmly believe we can break through the barriers and allow CAR-T/NKT therapy to benefit the vast majority of solid tumor patients."

Original Information

This article is based on the review "Decoding Signaling Architectures: CAR vs TCR Dynamics in Solid Tumor Immunotherapy" published by Researcher Xin Zhou's team in Acta Biochimica et Biophysica Sinica. It aims to popularize cutting-edge progress. Please be sure to follow the guidance of your attending physician for specific treatment plans.

Fulltext link: https://www.sciengine.com/ABBS/doi/10.3724/abbs.2025190