Cancer immunotherapy has transformed the treatment landscape for many patients with solid tumors, delivering durable responses in diseases that once resisted nearly every therapeutic approach. Yet the clinical success of immune checkpoint inhibitors, adoptive cell therapies, and other immuno-oncology strategies has exposed an uncomfortable truth: the laboratory models used to test these treatments before they reach patients are often inadequate proxies for the complex biology of human cancer. A new systematic review published in Cancer Immunology, Immunotherapy now offers the most comprehensive map to date of how researchers are using in vitro and ex vivo platforms to evaluate cancer immunotherapies, and it arrives at a moment when the field is urgently rethinking its preclinical toolkit.
The review, conducted by a team led by Giacomo Colella, Valentina Piccioni, and Gianmarco Contino of the University of Birmingham, adhered to the PRISMA 2020 reporting guidelines and searched the PubMed database for studies published between 2000 and 2025. The team focused specifically on in vitro and ex vivo models of solid tumors that had been tested in an immuno-oncology context, deliberately excluding animal studies to concentrate on human-relevant laboratory platforms. From this search, the researchers identified 75 studies that met their inclusion criteria, spanning six principal experimental model types and 23 different cancer types, with lung, breast, and colorectal cancers appearing most frequently in the literature.
The six model categories catalogued in the review represent a spectrum of biological fidelity and technical simplicity. Two-dimensional cell line cultures, the workhorse of cancer biology for decades, remain valuable for rapid initial screening of immunotherapeutic compounds. Three-dimensional spheroid cultures introduce a level of spatial organization that better recapitulates the architecture of tumors, including nutrient and oxygen gradients that influence immune cell behavior. Patient-derived organoids, or PDOs, go further by preserving many of the genetic and phenotypic characteristics of the original tumor from which they were grown, offering a personalized window into how an individual patient’s cancer might respond to immunotherapy.
At the ex vivo end of the spectrum, tumor tissue slices preserve the native architecture of the tumor microenvironment, including its stromal cells, extracellular matrix, and endogenous immune infiltrate, although they can typically be maintained in culture only for short windows of time. Tumor-on-a-chip systems, often built from polydimethylsiloxane or cyclic olefin copolymer, add another dimension of realism by enabling controlled perfusion, the establishment of chemical gradients, and the observation of immune cell trafficking under dynamic flow conditions that mimic the vasculature. The review also noted a residual category of other model types, including immune co-culture cell microarrays and platforms derived from circulating tumor cells or induced pluripotent stem cells.
On the immunotherapy side, the studies surveyed by the review interrogated a range of treatment modalities. Immune checkpoint inhibitors, particularly antibodies targeting the programmed death-1 receptor and its ligand PD-L1, dominated the landscape, reflecting their clinical prominence. Adoptive cell therapies formed the second major pillar, encompassing chimeric antigen receptor T cells, tumor-infiltrating lymphocytes, and natural killer cell-based approaches. The immune cell types most commonly incorporated into these experimental systems were T lymphocytes, including both tumor-infiltrating lymphocytes and CAR-T cells, followed by natural killer cells, a distribution that mirrors the current emphasis of clinical immuno-oncology.
A central theme of the review is the concept of transferability, meaning the degree to which findings generated in one model system can be generalized to other models, to different cancer types, and ultimately to patients. The authors recorded the culture setup, validation status, and species of origin for each study to enable contextual comparison across platforms. Their analysis suggests that no single model is sufficient on its own: two-dimensional cultures are useful for hypothesis generation and high-throughput screening, but they strip away the spatial and stromal context that governs immune cell function in real tumors. Three-dimensional spheroids and organoids restore much of that context, and organoids in particular retain patient-specific characteristics that make them attractive for precision immuno-oncology, yet they typically lack a complete immune component unless immune cells are deliberately co-cultured.
Tumor tissue slices occupy a distinctive niche because they retain the endogenous immune microenvironment, including tumor-associated macrophages, cancer-associated fibroblasts, regulatory T cells, and myeloid-derived suppressor cells, all of which are increasingly recognized as critical determinants of immunotherapy response and resistance. The limitation is practical rather than conceptual: slice viability declines over days, restricting the duration of experiments and complicating the assessment of therapies that require prolonged immune priming. Tumor-on-a-chip devices, by contrast, can sustain perfused cultures for longer periods and allow researchers to observe how immune cells migrate, extravasate, and infiltrate tumor tissue under physiologically relevant flow, but they demand specialized engineering expertise and remain difficult to standardize across laboratories.
The systematic nature of the review, prospectively registered with PROSPERO under registration number CRD420251153061, lends weight to its conclusions. The authors extracted data across defined domains including model type, immune cell representation, the class of immunotherapy assessed, and measures of transferability, summarizing the results into structured tables intended to serve as a practical reference. The work was supported by a Cancer Research UK Training Fellowship and by the European COST Action CA21135, and the authors acknowledged the Queen Elizabeth Upper Gastrointestinal Cancer Patient Group for its input. The team declared no competing interests, and because the review relied exclusively on publicly available published data, no primary patient samples or ethical approvals were required.
The practical significance of this catalogue lies in its potential to reduce the attrition that has plagued immuno-oncology drug development. Many immunotherapeutic agents that show promise in simplified laboratory systems fail in clinical trials, a pattern that experts attribute in part to the mismatch between conventional preclinical models and the immunologically complex reality of human tumors. By providing a curated, searchable dataset of 75 studies organized by model type, cancer type, immune context, and therapy class, the review gives researchers a tool for selecting the most appropriate platform for a given experimental question, whether that involves screening checkpoint inhibitor combinations in organoids, testing CAR-T cell cytotoxicity in spheroids, or probing immune trafficking in microfluidic chips.
The review also highlights gaps that the field must address. The representation of immune cell types remains narrow, with myeloid populations and dendritic cells underrepresented relative to T cells and natural killer cells, despite their established roles in shaping antitumor immunity. Validation standards vary widely across studies, and the authors note that culture conditions, extracellular matrix substitutes such as basement membrane extract, and air-liquid or gel-liquid interface techniques differ enough to complicate cross-study comparisons. As cancer immunotherapy continues to expand into new modalities and tumor types, the Birmingham team’s systematic inventory provides both a snapshot of current practice and a benchmark against which the next generation of preclinical platforms can be measured, bringing the laboratory one step closer to faithfully predicting which patients will benefit from the immune-based treatments reshaping modern oncology.
Subject of Research: A systematic review of in vitro and ex vivo preclinical models used to evaluate cancer immunotherapy in solid tumors
Article Title: Preclinical models for cancer immunotherapy: a systematic review of ex vivo and in vitro platforms
Article References: Colella, G., Piccioni, V., Swirsky, F., Kunene, V., & Contino, G. (2026). Preclinical models for cancer immunotherapy: a systematic review of ex vivo and in vitro platforms. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04494-w
Image Credits: AI Generated
DOI: 10.1007/s00262-026-04494-w
Keywords: cancer immunotherapy, patient-derived organoids, immune checkpoint inhibitors, CAR-T cells, tumor tissue slices, tumor-on-a-chip, 3D spheroids, tumor microenvironment, adoptive cell therapy, preclinical models, natural killer cells, systematic review
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Nathaniel Bowman. (September 12, 2026). Lab Models Take Center Stage in the Race to Improve Cancer Immunotherapy. Scienmag. https://scienmag.com/lab-models-take-center-stage-in-the-race-to-improve-cancer-immunotherapy/
Nathaniel Bowman. “Lab Models Take Center Stage in the Race to Improve Cancer Immunotherapy.” Scienmag, 12 September 2026, https://scienmag.com/lab-models-take-center-stage-in-the-race-to-improve-cancer-immunotherapy/. Accessed 12 September 2026.
Nathaniel Bowman. “Lab Models Take Center Stage in the Race to Improve Cancer Immunotherapy.” Scienmag. September 12, 2026. https://scienmag.com/lab-models-take-center-stage-in-the-race-to-improve-cancer-immunotherapy/
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