The work addresses a major limitation of chimeric antigen receptor, or CAR, T-cell therapy. In this treatment, a patient’s T cells are genetically equipped with synthetic receptors that recognize molecules on cancer cells. Once activated, the engineered immune cells attach to their targets and release toxic proteins that damage the cancer cell membrane and trigger cell death. CAR T therapy has produced dramatic results in several blood cancers, but solid tumors remain considerably more difficult to treat because their cells vary widely and are embedded in a complex physical environment that can restrict immune access and promote resistance.

The USC researchers focused on the mechanical properties of tumor cells and their surroundings. Earlier work from the Wang laboratory showed that cancer cells in soft environments can become less susceptible to CAR T-cell killing. The new study links this physical softness to the emergence of cancer stem-like features. These cells can self-renew and generate diverse tumor cell populations, making them important drivers of tumor growth, therapeutic resistance and relapse. Their deformable, springy nature may also make it harder for T cells to establish the firm physical contact required to attack them efficiently.

“Soft environment cancer cells typically have a greater tendency to become stem cell-like cells,” said Peter Yingxiao Wang, chair of the Alfred Mann Department of Biomedical Engineering at USC Viterbi. Unlike stiffer tumor cells, which CAR T cells can more readily engage and mechanically grasp, soft cells may be overlooked during immune surveillance. Lead author Jenny Yunjia Qu compared the problem to trying to pierce a gelatinous material such as Jello or tofu: the target yields rather than providing a stable surface for penetration. This physical mismatch can reduce the efficiency with which T cells form an immune synapse, deliver cytotoxic molecules and kill the cancer cell.

To identify these evasive cells, the team engineered a genetic device called the Mechano-Recorder. The system functions like a biological black box, recording the mechanical conditions experienced by a cell. The researchers found that cancer cells exposed to softer environments displayed substantially elevated intracellular calcium signaling. Calcium ions act as rapid biochemical messengers in many cellular processes, but these signals are normally transient and disappear after the stimulus ends. The Mechano-Recorder captures the calcium response and converts it into a persistent fluorescent signal, creating a stable molecular barcode for cells that have experienced softness.

This conversion allows researchers to identify cells according to a mechanical event that may have occurred hours or days earlier. The recorded signal revealed that softness-associated cells displayed characteristics commonly linked to aggressive disease, including stem-cell-like behavior and markers associated with hypoxia and metastasis. In this way, the tool does more than measure the physical environment in real time: it preserves a record of how that environment has altered cell state. Longwei Liu, an assistant professor of ophthalmology and biomedical engineering at USC and a study co-author, described the approach as taking a molecular snapshot of cancer cells for diagnostic or therapeutic development.

The researchers then rewired the recorder for treatment rather than observation. They replaced its fluorescent reporter with CD19, an antigen already used clinically as a CAR T-cell target in several blood cancers. When a soft, resistant cancer cell generated the relevant calcium signature, the engineered circuit triggered production of CD19 on its surface. The cancer cell was not naturally made more rigid or directly altered to become vulnerable in a physical sense. Instead, its mechanical history was translated into a recognizable molecular beacon. CD19-directed CAR T cells could then identify the reprogrammed cells and attack them selectively.

The strategy was tested in breast cancer cell lines, patient-derived cancer cells and mouse models. According to the researchers, tumors containing the rewired cells showed increased T-cell infiltration and improved killing of the previously resistant, soft cancer stem-like population. The approach was also evaluated in models of glioblastoma, pancreatic cancer and prostate cancer, suggesting that the underlying mechanism may extend beyond breast tumors. Because the system responds to a cellular signaling pathway rather than a cancer type-specific mutation, it could potentially be adapted to recognize other disease-associated states and connect them to therapeutic outputs.

The researchers emphasize that the findings represent a foundational preclinical concept rather than an approved treatment. The work demonstrates that a tumor’s physical properties can be recorded, interpreted and converted into instructions for immune targeting. A mechanical cue such as softness can therefore become an actionable biological signal: cells that once hid within a compliant tumor environment can be marked for destruction by engineered immune cells. The team believes the same design could eventually be adapted to translate other molecular signals into “kill me” or “help me” commands, offering a programmable route for improving immunotherapy against solid tumors.

Subject of Research: Softness-driven cancer stem-like cells and CAR T-cell resistance in solid tumors

Article Title: Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid tumours

News Publication Date: 6-Jul-2026

Web References: USC Viterbi School of Engineering; Keck School of Medicine of USC; Wang Lab; https://doi.org/10.1038/s41551-026-01722-7

References: Nature Biomedical Engineering, DOI: 10.1038/s41551-026-01722-7

Keywords: Cancer immunotherapy, CAR T-cell therapy, solid tumors, cancer stem-like cells, tumor softness, Mechano-Recorder, synthetic antigen, CD19, breast cancer, glioblastoma, pancreatic cancer, prostate cancer, biomedical engineering

A defining characteristic of the solid TME is profound hypoxia—an oxygen-deprived milieu that has been implicated in metabolic dysfunction and immune exhaustion of T cells. Experimental findings illustrate that under hypoxic conditions, CAR T cells rapidly diminish their effector capabilities while upregulating inhibitory receptors such as PD-1 and TIM-3, hallmarks of T cell exhaustion. This metabolic constraint coupled with intense immunosuppressive signaling compounds the difficulty of achieving durable tumor control.

Beyond hypoxia, the immune landscape of solid tumors is dominated by suppressive myeloid populations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cell types secrete inhibitory cytokines such as TGF-β and IL-10, which blunt cytotoxic T cell function. Furthermore, they manipulate the metabolic competition within the tumor niche by depleting essential nutrients like arginine and glucose, effectively starving T cells of critical resources necessary for their proliferation and persistence. This metabolic tug-of-war epitomizes the sophisticated tumor strategies to evade immunologic eradication.

Physical barriers imposed by the dense extracellular matrix and chaotic vasculature further restrict immune effector trafficking into the tumor core. Preclinical orthotopic models, notably in pancreatic and gastric cancers, demonstrate that CAR T cells preferentially accumulate at the tumor periphery, rarely infiltrating the densely packed core regions where malignant cells reside. This uneven distribution results in incomplete and heterogeneous tumor killing, thereby undermining the overall efficacy of the treatment. Coupled with this is the challenge of limited CAR T cell persistence in vivo: rapid expansion is often followed by contraction and eventual disappearance from circulation, paralleling tumor relapse and disease progression.

Another persistent challenge is antigen heterogeneity and specificity within solid tumors. Tumor-associated antigens like Claudin-18.2 and mesothelin, while promising targets, exhibit heterogeneous expression across cancer cell populations. This leads to selective pressure favoring antigen-negative clones, which expand and contribute to tumor escape. Moreover, many of these antigens are expressed at low levels in normal tissues, risking off-tumor, on-target toxicity. Clinical data from phase II trials targeting Claudin-18.2 vividly highlight this risk, showing significant gastric mucosal damage in a notable fraction of patients, underscoring the difficulty in identifying truly tumor-exclusive targets.

Adaptive immune resistance further complicates treatment outcomes. Tumors frequently evolve under immune pressure by altering antigen presentation pathways, enabling them to evade recognition and destruction by therapeutic T cells. The role of endogenous T cells in preventing antigen-loss mediated escape is increasingly clear, suggesting that single-antigen targeted therapies may be insufficient in isolation. Cytokine responses in the TME, particularly involving interferon-gamma (IFN-γ), embody a paradoxical role: while IFN-γ can enhance immune activation, it also induces immunosuppressive PD-L1 expression within the tumor, fostering a feedback loop of adaptive inhibition. This biological insight paves the way for rational combination therapies integrating immune checkpoint blockade with adoptive cell therapies.

Safety concerns remain a critical barrier to the broader application of ACT and ICEs in solid tumors. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are predominant adverse events arising from these therapies. These syndromes represent hyperinflammatory states driven by exuberant activation of immune effectors post-infusion, rather than mere dose-dependent toxicities. Their incidence correlates with tumor burden and baseline patient inflammatory milieu. Recent clinical trials of Claudin-18.2 CAR T cells report very high rates of CRS—exceeding 95%—although mostly mild-to-moderate in severity. BiTEs such as tarlatamab also induce substantial CRS rates, necessitating cautious dose escalation and inpatient monitoring protocols.

ICANS, while less frequent than CRS, poses significant clinical challenges due to its unpredictable neurological manifestations, including encephalopathy and seizures. Management often requires high-dose corticosteroids and temporarily halting therapy, complicating trial design and clinical management. Additionally, high-dose interleukin-2 (IL-2) administration following tumor-infiltrating lymphocytes (TIL) infusion triggers capillary leak syndrome (CLS), characterized by vascular permeability and hypotension, underscoring the delicate balance between therapeutic intensity and tolerability in ACT trials.

Compounding these acute toxicities is the emerging recognition of immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome (IEC-HS), a severe hyperinflammatory condition marked by cytopenias, coagulopathy, and multiorgan dysfunction, often manifesting during the resolution phase of CRS. Its management frequently necessitates intensified immunosuppressive strategies, including high-dose steroids alongside agents such as anakinra and ruxolitinib. The acknowledgment of IEC-HS as a discrete clinical entity has informed evolving toxicity mitigation frameworks, aiming to maximize therapeutic benefit while minimizing life-threatening adverse events.

The innovation in immunotherapy has been paralleled by the development of strategies to mitigate these toxicities. Step-up dosing regimens for T cell engagers and selective corticosteroid prophylaxis in high-risk cohorts are becoming integral components of clinical protocols, striving to strike a balance between efficacy and safety. These approaches reflect an increasingly nuanced understanding of the inflammatory cascades unleashed by immune therapies and a commitment to enhancing patient outcomes.

Manufacturing complexities add another dimension to the challenges faced in solid tumor immunotherapy. Adoptive cell therapy often involves labor-intensive, patient-specific processes of T cell isolation, genetic modification, expansion, and quality control. Variability in expansion potential attributable to individual donor variability and T cell fitness foreshadows significant scalability and cost hurdles. Clinical translation will necessitate innovations in manufacturing to enable broad accessibility and economic viability.

As research advances, it becomes clear that overcoming the solid tumor microenvironment’s multifactorial resistance mechanisms demands multidimensional approaches. Incorporating metabolic reprogramming, improving trafficking, selecting optimal antigen targets, and developing robust combinatorial regimens including checkpoint inhibitors are essential. Equally important is refining dosing paradigms and supportive care to mitigate toxicities without blunting therapeutic efficacy.

In summary, while adoptive cell therapies and immune cell engagers have revolutionized hematologic cancer treatment, their application in solid tumors remains beset by formidable biological barriers and safety concerns. Progress hinges on a deep mechanistic understanding of the tumor microenvironment and immune dynamics, alongside innovative clinical strategies to enhance trafficking, persistence, and antigen specificity. Coupled with careful toxicity management and manufacturing advancements, these efforts are poised to unlock the full potential of immunotherapy for patients battling solid malignancies.

The emerging paradigm underscores the essential interplay between tumor biology, immune evasion, and therapeutic design. By unraveling these complex interactions and tailoring interventions accordingly, the field stands on the threshold of transforming the landscape of solid tumor cancer therapy, offering renewed hope for durable remission and improved survival outcomes.

Subject of Research: Advances in cancer immunotherapy focusing on adoptive cell therapy and immune cell engagers for solid tumors.

Article Title: Advances in cancer immunotherapy: adoptive cell therapy and immune cell engagers in solid tumours.

Article References:
Panasci, J., Park, C.L., Tran, B. et al. Advances in cancer immunotherapy: adoptive cell therapy and immune cell engagers in solid tumours. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03450-w

Image Credits: AI Generated

DOI: 27 April 2026