Chimaeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of several blood cancers, but its effectiveness against solid tumours has remained limited.

A new review published in Oncoscience was led by first and corresponding author Samuel Obiosa Onyekweli from the Department of Internal Medicine, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria.

A meta-analysis cited in the review estimated a pooled objective response rate of approximately 9% for CAR-T therapy in solid malignancies, highlighting the large efficacy gap between solid and hematologic cancers.

The authors explain that this gap is driven by several interacting barriers rather than a single obstacle.

CAR-T cells must penetrate dense tumour stroma and abnormal vasculature, survive nutrient depletion and hypoxia, overcome immunosuppressive signals, recognise heterogeneous tumour antigens, and resist progressive exhaustion.

The review therefore frames the solid tumour microenvironment as a collection of distinct engineering problems that can potentially be addressed through coordinated design.

One of the review’s central themes is a shift from maximising T-cell potency toward building cellular resilience.

Earlier CAR-T approaches largely focused on stronger activation and costimulatory signalling, whereas newer strategies aim to protect engineered T cells from the hostile conditions encountered inside solid tumours through metabolic armoring, epigenetic protection, improved trafficking, and resistance to suppressive signalling.

T-cell exhaustion is a major part of this challenge.

Chronic stimulation can progressively lock CAR-T cells into dysfunctional transcriptional states.

The review discusses strategies including c-Jun overexpression to restore AP-1-dependent transcription, DNMT3A disruption to interfere with epigenetic exhaustion programmes, cytokine armoring with IL-10, IL-15, IL-18, or IL-21 to support cellular fitness, and dominant-negative receptors such as dnTGF-βRII to shield CAR-T cells from immunosuppressive signalling.

Other engineering approaches address tumour access and targeting specificity.

Chemokine receptors such as CCR2b can improve tumour trafficking, while hypoxia-responsive CARs exploit low-oxygen conditions to restrict activity toward the tumour environment.

Synthetic biology platforms, including synNotch AND-gates, Tmod NOT-gates, and drug-controlled CAR systems, add further control by requiring specific molecular conditions before engineered T cells become fully active.

The authors argue that recent clinical developments suggest that some of these engineering principles are beginning to translate into meaningful outcomes.

In H3K27M-mutated diffuse midline glioma, intracerebroventricular GD2-targeted CAR-T therapy produced major tumour reductions, including a complete response sustained beyond 30 months.

In advanced gastric cancer, CLDN18.2-targeted satricabtagene autoleucel, or satri-cel, demonstrated superiority over physician’s choice in a randomised Phase 2 trial, with a progression-free survival hazard ratio of 0.37 and an overall survival hazard ratio of 0.69.

The review describes this as the first evidence of randomised CAR-T superiority over standard treatment in a solid malignancy.

Another notable example comes from hepatocellular carcinoma.

GPC3-targeting C-CAR031 incorporates a dominant-negative TGF-β receptor to protect CAR-T cells from immunosuppressive signalling and achieved reported objective response rates of approximately 50–57%.

However, the authors emphasise that these efficacy results currently derive from conference abstracts and await full peer-reviewed publication.

Beyond engineering the CAR-T cell itself, the review expands the therapeutic framework to the broader biological environment of the patient.

Factors such as the gut microbiome, conditioning regimen, manufacturing duration, T-cell phenotype at infusion, and systemic neuroendocrine signalling may also influence CAR-T persistence and fitness.

The authors argue that successful solid-tumour CAR-T therapy may therefore require optimisation of the engineered cell, the tumour microenvironment, and the patient’s broader physiological context.

Manufacturing is another major frontier.

The review discusses next-day manufacturing approaches and emerging platforms that could generate CAR-T cells directly inside the patient using targeted lipid nanoparticles or receptor-targeted lentiviral particles.

These technologies could eventually reduce manufacturing complexity and broaden access, although their regulatory and clinical pathways are still being defined.

“The path forward requires not merely applying hematologic paradigms to solid tumours, but fundamentally reconceptualizing the T cell as a drug product that must be delivered to the right compartment, armoured against suppression, and integrated into a holistic therapeutic system that includes manufacturing optimisation, microbiome stewardship, systemic physiological context, and rational combination strategies.”

To organise these advances, the authors propose a four-tier framework for future solid-tumour CAR-T development.

The first tier focuses on delivery, including locoregional administration for difficult-to-access tumours.

The second emphasises resilience, using armoring strategies to protect CAR-T cells from immunosuppressive environments.

The third focuses on logic, using advanced targeting circuits to improve specificity.

The fourth expands the concept to the entire system, incorporating factors such as the microbiome, conditioning, manufacturing, T-cell phenotype, and systemic physiology.

Despite recent progress, the authors emphasise that major questions remain unresolved.

Long-term genomic stability after multiplex gene editing has not been established, sustained cytokine armoring introduces potential safety concerns, and increasingly complex CAR-T constructs create manufacturing and regulatory challenges.

Biomarker-guided selection of specific engineering strategies also remains an aspirational approach that will require prospective clinical validation.

Overall, the review presents solid-tumour CAR-T therapy as moving from a strategy centred mainly on increasing T-cell potency toward one built around integrated, resilience-based engineering.

By treating trafficking, metabolic stress, immune suppression, antigen heterogeneity, and epigenetic exhaustion as distinct but interconnected challenges, the authors outline a more systematic path toward next-generation CAR-T therapies.

Recent clinical results are encouraging, but larger studies, longer follow-up, and rigorous validation will be needed to determine which strategies can produce durable benefits across different solid tumours.

Source: Oncoscience