In the rapidly evolving field of cancer immunotherapy, adoptive cell therapy (ACT) and immune cell engagers (ICEs) are carving out promising new frontiers, particularly for the notoriously challenging landscape of solid tumors. Despite their revolutionary potential witnessed in hematologic malignancies, translating these advances to solid tumors continues to confront formidable biological and clinical barriers. The immunosuppressive tumor microenvironment (TME) emerges as a pivotal antagonist, orchestrating a multifaceted defense against immune effector cells and severely hampering the sustainable activity of therapeutic approaches like chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs).
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
