Engineered T Cell Receptors With Built-In ICOS Deliver Long-Lasting Anti-Tumor Power

Adoptive T cell therapy has delivered striking remissions in some blood cancers, but its promise in solid tumors has been repeatedly undermined by a stubborn problem: the therapeutic cells do not last. Engineered T cells that flood a tumor and then fade away, or that settle into a dysfunctional, exhausted state, leave the door open for relapse. A team of researchers at Erasmus MC Cancer Institute in Rotterdam, working with colleagues at Pan Cancer T BV and the Department of Immunology at Erasmus MC, now reports a design solution that attacks the longevity problem at its source. In a study published in Molecular Cancer, the group describes a rebuilt T cell receptor that carries its own co-stimulatory machinery, and shows that the resulting cells mount exceptionally durable anti-tumor responses in a mouse melanoma model, including delayed tumor recurrence and outright cures.

The core idea is deceptively simple. Natural T cells do not rely on their antigen receptor alone; they depend on co-stimulatory receptors such as CD28 and ICOS, the inducible T cell co-stimulator, to fine-tune activation, survival and differentiation. The researchers reasoned that if a therapeutic T cell receptor could be fused directly to a co-stimulatory signaling domain, every encounter with a tumor cell would deliver not just a recognition signal but a survival and persistence signal at the same time. The construct they engineered, which they call TCR:ICOS, combines the extracellular variable and constant domains of a conventional T cell receptor with a CD28 transmembrane segment and intracellular domains drawn from both ICOS and CD3 epsilon. The result is a single hybrid receptor that couples antigen specificity to co-stimulation in one molecular unit.

The functional consequences in mice were dramatic. T cells carrying the TCR:ICOS receptor showed enhanced, antigen-specific production of inflammatory cytokines, the chemical weapons that help recruit and coordinate an immune attack. More importantly, the cells persisted far longer within tumors than their conventional counterparts, and this persistence translated into clinical outcomes: delayed recurrence of melanoma and, in a subset of animals, complete and durable cures. For a field in which the transience of engineered T cells is a central bottleneck, the demonstration that a receptor-level modification can extend the working lifespan of the cells inside a hostile tumor microenvironment is a significant proof of concept.

Beneath the phenotypic changes lies a defined signaling logic. The team found that TCR:ICOS activation engaged two major pathways, PI3K and NF-kappa B, while paradoxically restraining the activation of AKT, a kinase downstream of PI3K that is often associated with terminal differentiation and metabolic burnout in T cells. This combination appears to be the key to the durability. Sustained PI3K and NF-kappa B signaling supports inflammatory function and survival, while blunted AKT activity helps the cells avoid the hyperactive, exhausted state that typically shortens the life of tumor-infiltrating lymphocytes. When the researchers genetically ablated the ICOS-PI3K pathway, the long-term anti-tumor effects disappeared, confirming that this signaling axis is not a side effect but the mechanistic engine of the durable response.

Single-cell level analysis reinforced the picture of a fundamentally altered differentiation program. TCR:ICOS T cells were enriched for a stem-like state, a less differentiated, self-renewing condition that immunologists regard as the hallmark of long-lived, re-challenge-capable T cell populations. They also showed resistance to exhaustion, the progressive loss of function marked by inhibitory receptors such as PD1, LAG3 and TIM3 that plagues conventional tumor-infiltrating cells. In practical terms, the engineered cells behaved less like short-lived commandos and more like a renewable garrison, capable of maintaining pressure on the tumor over time rather than expending themselves in a single burst of activity.

Translating the concept from mouse to human T cells required an additional round of molecular engineering. Early versions of the hybrid receptor did not express efficiently on the surface of human cells, a common obstacle in receptor design where folding, assembly and trafficking can fail silently. The team solved this by identifying a single amino acid change in the cytosolic tail of the receptor that enabled functional surface expression. Crucially, the optimized receptor avoided two well-known hazards of introducing engineered T cell receptors into patient cells: mispairing with endogenous TCR chains, which can create unpredictable and potentially dangerous specificities, and competition for limited CD3 molecules, which can impair the function of the T cell’s native receptor complex.

The human-cell experiments went beyond a single antigen. The researchers showed that the optimized TCR:ICOS format sustained the functional performance of human T cells across repeated stimulation cycles and could be extended to multiple tumor antigens, including targets relevant to solid cancers such as NY-ESO-1 and ROPN1, without eroding T cell fitness. This uniform applicability matters for the field. Many receptor-engineering advances are idiosyncratic, working for one TCR or one antigen but failing when generalized. A format that preserves T cell quality across different specificities offers a modular platform: any tumor-reactive TCR could, in principle, be equipped with the same built-in co-stimulation and inherit the same durability advantages.

The findings arrive at a moment when the cell therapy field is intensely focused on next-generation designs. Chimeric antigen receptors, or CARs, already incorporate co-stimulatory domains such as CD28 or 4-1BB, and that choice profoundly shapes how CAR T cells persist and differentiate. TCR-based therapies, which can recognize intracellular tumor antigens presented by HLA molecules and therefore access a much larger pool of cancer targets, have lacked an equivalent, systematic way to embed co-stimulation. The TCR:ICOS design fills that gap, and its mechanism, favoring stem-like persistence through PI3K and NF-kappa B while restraining AKT, offers a template that other groups can rationally modify.

There are, of course, steps between a mouse melanoma model and approved therapy. The study was conducted in preclinical systems, and human trials will need to establish safety, particularly given that engineered co-stimulation could, in principle, amplify off-tumor reactivity if a TCR recognizes healthy tissue. Dosing, manufacturing consistency and the behavior of TCR:ICOS cells in the complex, immunosuppressive environment of human solid tumors all remain to be tested. The authors note that the work was supported by the Dutch Cancer Society and a Health Holland public-private partnership, and several team members report pending patents related to the receptor design, signaling commercial interest in bringing the platform toward clinical evaluation.

Even so, the study offers a compelling answer to one of adoptive cell therapy’s most persistent questions: how to make engineered T cells last. By fusing recognition and co-stimulation into a single receptor, the Rotterdam team has shown that durability can be designed into the therapeutic product itself rather than bolted on with cytokines, checkpoint blockade or lymphodepleting chemotherapy. If the format performs in human trials as it has in mice, TCR:ICOS could become a foundational component of fitter, longer-lived T cell products for solid tumors, turning a transient spark of immune attack into a sustained campaign against cancer.

Subject of Research: Engineering T cell receptors with built-in ICOS co-stimulation to extend the durability of adoptive T cell therapy against solid tumors

Article Title: T cell receptors equipped with ICOS provide T cells with durable anti-tumor response

Article References: Marraffa, A., Berrevoets, C., Mosiello, M., Coelho, R. M., Roelofs, D., van Brakel, M., Wijers, R., Kroese, K., Peeters, M. J., Dik, W. A., Kunert, A., Abbott, R. J., Hammerl, D., Schliehe, C., & Debets, R. (2026). T cell receptors equipped with ICOS provide T cells with durable anti-tumor response. Molecular Cancer, 25(1), Article 216. https://doi.org/10.1186/s12943-026-02765-9

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02765-9

Keywords: adoptive T cell therapy, T cell receptor, ICOS, co-stimulation, T cell exhaustion, solid tumors, melanoma, PI3K signaling, NF-kappa B, stem-like T cells, gene engineering, Molecular Cancer