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Open research questions in Immune cells in cancer

82 unresolved questions extracted from the limitations and future-work sections of 311 Immune cells in cancer papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood.

    MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma · 2026 · DOI

  • Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that remains difficult to treat despite its relatively high immunogenicity, as tumors frequently evade immune destruction through poorly understood mechanisms.

    Genetic and Pharmacologic Targeting of Eya3 in Macrophages Drives Anti-Tumor Immunity in Triple-Negative Breast Cancer · 2026 · DOI

  • Cell competition is an evolutionarily ancient biological mechanism that has been co-opted by breast cancer to drive clonal evolution, BCSC maintenance, immune evasion and therapeutic resistance. Within the breast cancer TME, cancer stem cells exploit MYC amplification, Hippo/YAP pathway dysregulation, Wnt and Notch signaling and metabolic Warburg strategy to achieve supercompetitor status that enables their selective survival and expansion within a diverse cellular ecosystem. Immune cell populations including TAMs, CTLs, NK cells, Tregs, and MDSCs engage in intricate competitive dynamics for niche resources, with the progressive competitive displacement of anti-tumor immune populations by pro-tumor immunosuppressive cells representing a defining feature of breast cancer immune evasion. CAFs and the ECM provide the non-cellular competitive infrastructure that supports BCSC dominance and immune exclusion. Probabilistic and spatial mathematical models are beginning to quantify these competitive dynamics and predict therapeutic outcomes. Translating the cell competition framework into clinical practice requires the development of novel combination therapeutic strategies that simultaneously target multiple levels of competitive regulation within the breast cancer TME. Immune checkpoint inhibitors that restore CTL competitive balance, combined with BCSC-targeting agents that reduce cancer stem cell competitive fitness, metabolic reprogramming strategies that relieve the immunosuppressive competitive metabolic environment and CAF/ECMmodifying agents that dismantle the competitive infrastructure of the desmoplastic stroma, represent a rational combinatorial framework derived from competitive principles.

    Cell competition within breast tumor microenvironment: emerging role of cancer stem cells and immune cells in tumor progression and therapeutic implications · 2026 · DOI

  • Antigen-presenting cell (APC) interactions with cytotoxic T cells are critical for anti-tumour immunity and response to immune checkpoint blockade (ICB), yet context-specific regulators in the tumour microenvironment remain not fully defined.

    SIGLEC1 FACILITATES MACROPHAGE-CD8+ T CELL INTERACTIONS AND CORRELATES WITH CANCER IMMUNOTHERAPY RESPONSE · 2026 · DOI

  • In the skin, Toll-like receptor 4 (TLR4) has been associated with tumorigenesis; however, its epithelial-intrinsic role in regulating microbiota-driven squamous cell carcinoma (SCC) initiation remains poorly defined.

    Abstract B017: TLR4 loss and IKKα haploinsufficiency drive bacterial dysbiosis and IL-4R–mediated squamous carcinogenesis in skin 3D organoids · 2026 · DOI

  • Tumor-associated macrophages (TAMs) are abundant in intrahepatic cholangiocarcinoma (ICC) and correlate with poor prognosis, but their non-immunosuppressive roles remain unclear.

    VEGFA+ macrophages promote the growth and metastasis of intrahepatic cholangiocarcinoma via OSM and THBS1 signaling · 2026 · DOI

  • Inflammatory bowel disease (IBD) arises from dysregulated crosstalk between innate immune, adaptive immune, and stromal compartments, yet the compartment-specific mechanisms driving tissue injury and tumorigenesis remain incompletely defined.

    Lamin A/C regulates the compartment-specific contributions of immune and stromal cells to intestinal inflammation and colitis-associated colon cancer · 2026 · DOI

  • Type I interferons (IFN-I) and IFN{gamma} exert divergent effects during tuberculosis, but the mechanisms that determine whether macrophage activation promotes host defense or inflammatory pathology remain incompletely understood.

    IFN and IFN mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation · 2026 · DOI

  • The computational study of immune cell trafficking and the tumour microenvironment is a rapidly advancing field, propelled forward by developments in artificial intelligence, single-cell omics technologies, and increasingly sophisticated computational frameworks backed by experimental validation (147, 190). Looking ahead, the field will largely focus on tackling persistent challenges in precision, resolution, and the interpretability of complex model outputs. AI-driven immune modelling is now advancing through the integration of fundamental models with large-scale multi-omics data, including transcriptomics, proteomics, metabolomics, etc. (191). All of these will be combined to predict immune trafficking at an unpredictable resolution. For instance, tools such as graph neural networks will learn to represent TME cell-to-cell communications, enabling zero-shot prediction of interactions between novel chemokine receptors and cross-linking checkpoints (81). Generative AI will synthesize artificial datasets to manage problems such as limited clinical samples and overfitting in rare types of tumours (192). Some AI methods, such as SHAP and attention mechanisms, can credibly enhance the interpretation of such predictions, revealing whether trafficking is being restored or evaded (193).

    A review on in-silico analysis of immune cell trafficking and interactions with the tumour microenvironment · 2026 · DOI

  • A key limitation is our incomplete 469 understanding our incomplete understanding of how the spatial organization of the TME 470 influences the functional capacity of tumor-infiltrating lymphocytes.

    Spatial architecture of the melanoma immune niche reveals CORO1A as a functional hub for T cell cytotoxicity and immunotherapy synergy · 2026 · DOI

  • Abstract Epidural fibrosis (EF) is a frequent and debilitating complication that impairs recovery following spinal surgery, yet effective targeted therapies are lacking.

    Bispecific antibody engineered extracellular vesicles redirect T cells to prevent postoperative epidural fibrosis · 2026 · DOI

  • BackgroundProtein fibrillation represents a critical challenge in therapeutic insulin delivery, yet the structural determinants and immunological consequences of insulin-derived fibrils (IDFs) formed in the presence of phenolic preservatives remain poorly characterized.

    Immunomodulatory Effects of Insulin-Derived Fibrils from Infusion Pumps: Role of Phenolic Preservatives in Macrophage Activation · 2026 · DOI

  • Culturing bone marrow (BM) with granulocyte macrophage-colony stimulating factor (GM-CSF) is the most commonly used standard method of generating mouse dendritic cells (DCs) in vitro , although the development of those MHC II hi GM-CSF–induced DCs (GM-DCs) remains poorly elucidated.

    CD32b defines distinct dendritic cell lineages generated from the culture of bone marrow with GM-CSF · 2026 · DOI

  • Nevertheless, scRNAseq has not yet led to a clear immunophenotypic characterization of PMN-MDSCs, and clinical relevance by functional testing is still lacking.

    Identification of immunosuppressive neutrophils using multi-omics: why functional testing remains key · 2026 · DOI

  • However, the specific functions of their cellular subsets and the alterations that occur in the context of osteoporotic fracture (OPF) remain poorly elucidated.

    Monocyte cluster identification during the early stage of fracture healing in an ovariectomized mouse model · 2026 · DOI

  • Among these, colony-stimulating factors--particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF or CSF3)--regulate myeloid cell behavior during cancer progression, although their specific roles in melanoma remain unclear.

    G-CSF associates with poor survival in cutaneous melanoma and promotes metastasis through coordinated effects on macrophages and tumor cells · 2026 · DOI

  • Therapeutic resistance is increasingly recognized as an ecosystem-level process rather than a purely tumor-cell-intrinsic event.

    Immune–tumor cell ligand–receptor axes driving metabolic reprogramming and therapeutic resistance in cancer · 2026 · DOI

  • Although existing studies have elucidated the binding specificity of VISTA and associated signaling pathways across different cell types, the molecular mechanism by which VISTA switches between inhibitory and stimulatory signaling on different cell surfaces using the same extracellular domain structure remains to be elucidated (25,117).

    Roles of V‑domain Ig suppressor of T‑cell activation‑mediated immunoregulation in tumor immune escape (Review) · 2026 · DOI

  • Osteosarcoma is a highly invasive and easily metastatic malig- nant bone tumour that has long posed significant treatment challenges, particularly with regard to metastasis and recurrence. Although traditional strategies combining surgery and chemother- apy have significantly improved survival rates for patients with early-stage disease, they are less effective for those with advanced or metastatic disease. This has prompted a shift in research towards the critical area of the tumour microenvironment. In recent years, TAM has become a key breakthrough in understanding the pro- gression mechanisms of osteosarcoma and in developing novel therapies, as it is one of the most important immune infiltrating cells. Here, we systematically elucidate the role of macrophage polarisation in the development and progression of osteosarcoma. Overall, TAMs convert into the pro-tumour M2 phenotype under the stimulation of specific microenvironments (such as IL-4 and IL- 13). This subsequently drives the malignant progression of osteo- sarcoma through a network mechanism that promotes growth and proliferation, immune evasion, angiogenesis and distant metastasis. In terms of growth and reproduction, TAM of the M2 type can stimulate the proliferation of osteosarcoma and resist apoptotic signals by directly secreting growth factors, such as EGF and FGF, or by delivering exosomes that activate the AKT signalling pathway. In the context of immune evasion, M2-like TAMs directly inhibit the function of T and NK cells by expressing high levels of ligands such as CD47 and PD-L1, and by secreting immunosuppressive factors such as TGF-b and IL-10. They also recruit Tregs, collec- tively constructing an immunosuppressive microenvironment that enables tumour cells to evade immune surveillance. Furthermore, TAM of the M2 type can secrete IL-18, IL-22 and MMPs, which effectively induce EMT and degrade the extracellular matrix.

    From mechanism to therapy: advances in macrophage polarisation and targeted intervention in osteosarcoma · 2026 · DOI

  • Second, the broader molecular mechanisms by which ZNF750 orchestrates the esophageal mucosal immune landscape and the host-microbe interface remain to be fully elucidated and require more in-depth experimental validation.

    ZNF750 suppresses esophageal squamous cell carcinoma by maintaining epithelial barrier–driven mucosal immune homeostasis · 2026 · DOI

  • Macrophage polarization is intrinsically linked to metabolic reprogramming. Pro-inflammatory macrophages rely on enhanced glycolysis, which sustains the production of inflammatory mediators such as TNF-a, IL-1b, and ROS. In contrast, anti-inflammatory macrophages predominantly utilize OXPHOS and fatty acid oxidation to support their reparative and immunoregulatory functions. These distinct metabolic programs not only meet the specific energetic demands of each phenotype but also actively shape macrophage effector responses, thereby influencing the trajectory and resolution of inflammatory processes during S-ALI (207, 208). As sepsis progresses, the metabolic landscape of macrophages undergoes dynamic temporal shifts: the early hyperinflammatory phase is characterized by enhanced glycolysis, while the late immunosuppressive phase exhibits impaired OXPHOS and FAO, with profound defects in the carnitine shuttle observed specifically in non-survivors (62, 160). This biphasic metabolic trajectory underscores the necessity of considering disease stage when designing therapeutic interventions. The traditional M1/M2 binary classification, while heuristically useful, warrants critical reflection. As discussed above, macrophage activation in vivo encompasses a fluid continuum of functional states shaped by the convergence of diverse signals, intracellular pathways, and epigenetic modifications (34–36). The binary model, despite its experimental convenience, fails to capture the intermediate and hybrid phenotypes that are particularly prevalent in complex inflammatory environments such as the septic lung. A related and equally important consideration is the heterogeneity of macrophage populations within the lung (209). Alveolar macrophages, interstitial macrophages, and recruited monocyte-derived macrophages possess distinct developmental origins, transcriptional programs, and homeostatic functions. However, the extent to which these subpopulations undergo divergent metabolic reprogramming during S-ALI remains poorly characterized. In the current literature, most mechanistic insights have been derived from reductionist models employing BMDMs, peritoneal macrophages, or immortalized cell lines, and it remains unclear how faithfully these systems recapitulate the metabolic behavior of specific lung-resident subsets. Moreover, local microenvironmental factors, including oxygen tension, pH, nutrient availability, and extracellular matrix composition, are likely to exert profound influences on macrophage metabolism within different compartments of the injured lung, yet these variables are rarely considered in experimental designs.

    Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies · 2026 · DOI

  • Immunosuppressive cells within the TME—including Treg cells, MDSCs, TAMs and TANs—exhibit remarkable metabolic plasticity that enables them to thrive under nutrient-deprived, hypoxic and acidic conditions. By contrast, effector immune cells such as CD8⁺ T cells and NK cells are metabolically disadvantaged in this hostile environment, leading to impaired function and reduced antitumor efficacy. This metabolic antagonism is a critical barrier to the success of current immunotherapies. Recent studies have highlighted how these suppressive popula- tions exploit key metabolic pathways—such as FAO, glycolysis, amino acid catabolism and lactate utilization—to maintain their immunosuppressive phenotypes. Moreover, the TME is shaped by metabolic byproducts such as lactate, ROS and adenosine, which further inhibit effector cell function and reprogramming. These insights have opened new avenues for metabolic intervention to reprogram the immune landscape of tumors. Experimental & Molecular Medicine function. Second, Moving forward, several critical areas warrant further investi- gation. First, there is an urgent need to identify context-specific metabolic checkpoints that selectively impair suppressive cells without compromising effector cell the development of metabolic imaging tools and spatial metabo- lomics will be essential the dynamic interplay to decipher between immune cell subsets in vivo. Third, combinatorial integrating metabolic modulators with immune strategies checkpoint therapies should be inhibitors or adoptive cell systematically evaluated to overcome resistance mechanisms and enhance durable responses. Fourth, some compounds may have off-target effects, for example, although inhibition of long- chain FAO with etomoxir has been widely used to dissect the metabolic role of FAO in lymphocytes, Raud, O’Connor and colleagues demonstrated—using Cpt1a genetic ablation models —that the effects of etomoxir on T cell differentiation and function are independent of Cpt1a expression122,123. This finding highlights the potential for off-target effects of etomoxir on cellular metabolism, particularly when used at high concentra- tions. Finally, translating these findings into clinically actionable biomarkers and therapies will require a multidisciplinary approach encompassing immunology, oncology, systems biol- ogy and bioengineering. Ultimately, targeting the unique metabolic vulnerabilities of immunosuppressive cells represents a promising strategy to tip the immunological balance in favor of antitumor immunity and improve patient outcomes across a broad spectrum of cancers. REFERENCES 1. Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024). 10 J. Kim et al. 2. Lim, S. A. Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy. BMB Rep. 57, 388–399 (2024). 33. Wan, Y. Y. Regulatory T cells: Immunol. 7, 204–210 (2010). immune suppression and beyond. Cell Mol. 3. Baghban, R. et al. Tumor microenvironment complexity and therapeutic impli- 34. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by cations at a glance. Cell Commun Signal 18, 59 (2020). 4. Poyia, F., Neophytou, C. M., Christodoulou, M. I. & Papageorgis, P. The role of tumor microenvironment in pancreatic cancer immunotherapy: current status and future perspectives. Int. J. Mol. Sci. (2024). the transcription factor Foxp3. Science 299, 1057–1061 (2003). 35. Dikiy, S. et al. A distal Foxp3 enhancer enables interleukin-2 dependent thymic Immunity 54, lineage commitment for robust immune tolerance.

    Metabolic adaptations of immunosuppressive cells in cancer: mechanisms and therapeutic targets · 2026 · DOI

  • such as the ENO2-MIF axis. Meanwhile, several should be noted. First, our discovery scRNA-seq cohort included only 6 patients, and the prognostic and predictive value of ENO2 needs to be validated in large-scale, multi-center clinical cohorts. Second, all enrolled patients were treatment-naive without neoadjuvant chemoradiotherapy, so the impact of systemic treatment on the ENO2-MIF axis remains unclear, which may affect its clinical application in pre-treated patients.31 Third, our study focused exclusively on liver metastasis, and the role of the ENO2-MIF axis in other distant metastatic sites of CRC lung, peritoneum) has not been explored. Finally, the (e.g., specificity and clinical safety of the ENO2-MIF interaction inhibitor pyrithioxin need further optimization and validation in preclinical studies.

    ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis · 2026 · DOI

  • The dynamic crosstalk and competition between specialized TAM subsets and their compositional shifts during recurrence towards BMDM-dominated pools need deeper mechanistic investigation.

    Spatiotemporal and metabolic heterogeneity of tumor-associated macrophages in glioblastoma: from single-cell insights to therapeutic targeting · 2026 · DOI

  • The complex spatial logic of TAM localization guided by metabolic demands, structural cues, and tumor-derived signals requires further elucidation beyond current understanding of context-dependent enrichment.

    Spatiotemporal and metabolic heterogeneity of tumor-associated macrophages in glioblastoma: from single-cell insights to therapeutic targeting · 2026 · DOI

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82 open questions have been extracted from the limitations and future-work passages of 311 Immune cells in cancer papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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