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Open research questions in Cancer Cells and Metastasis

84 unresolved questions extracted from the limitations and future-work sections of 382 Cancer Cells and Metastasis papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Abstract Background Cancer-associated fibroblasts (CAFs) promote colorectal cancer (CRC) progression through immunosuppression, but their functional heterogeneity and specific mechanisms in recruiting myeloid cells remain poorly defined.

    ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion · 2026 · DOI

  • These findings support further investigation of GDF15-directed and mitochondria-targeted strategies to overcome CAF-associated treatment resistance in esophageal adenocarcinoma.

    Targeting the CAF-GDF15 axis attenuates AKT-mediated mitochondrial rewiring and chemoradiation resistance in esophageal adenocarcinoma · 2026 · DOI

  • Finally, although our findings suggest that PIGT may play an important role in tumor–immune interactions, the precise biochemical pathways and signaling mecha- nisms involved remain to be elucidated.

    Single-cell and spatial transcriptomic landscapes reveal PIGT as a pivotal regulator of immunometabolic remodeling in colorectal cancer liver metastasis · 2026 · DOI

  • Regarding primary cancer and metastasis, each cell type is clinically recognized through histopathology, immunohistochemistry, and molecular biology, but their collective effects remain to be parsed. Epithelial cancer and distant metastasis involve highly heterogeneous cancer cells, CAFs, MAFs, cell components, signaling, and crosstalk, which remain incompletely understood in the context of how their interactions promote disease.

    Epistemology of the Origin of Cancer IV: Predisposing Conditions for Metastases · 2026 · DOI

  • Although distinct EMT-associated states have been linked to invasive and metastatic behavior, it remains unclear when these states arise during primary tumor progression, how they diversify, and whether metastatic competence is restricted to a particular EMT phenotype.

    Multiple distinct metastatic cell states are induced by epithelial-mesenchymal plasticity · 2026 · DOI

  • Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce.

    An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases. · 2026 · DOI

  • Although the immunological features of fully epithelial or fully mesenchymal tumor states have been characterized, the immune landscape associated with intermediate or partial EMT states remains poorly understood.

    Epithelial-mesenchymal transition is associated with altered immune composition and cytotoxic function in triple-negative breast cancer · 2026 · DOI

  • Background: Mechanical forces, particularly tensile stress, influence tumor progression by modulating cancer-associated fibroblast (CAF) behavior and extracellular matrix remodeling, yet their role in oral cancer remains insufficiently defined.

    In vitro effects of tensile strain on cancer-associated and matched normal fibroblasts derived from oral squamous cell carcinoma: an exploratory study · 2026 · DOI

  • Although the utilization of patient-derived and ectopically derived xenograft models (12, 13, 15–19) has been critical for our current understanding of CIC::DUX4 biology, these models are limited by the absence of an intact immune system, the bypassing of tumor initiation steps, and the presence of a non-native tumor microen- vironment.

    Targeting CIC::DUX4 sarcoma with Minnelide in a dual recombinase-initiated genetically engineered mouse model · 2026 · DOI

  • Glandular architecture - the coordination of lumen-containing structures by an apical-basal polarised epithelium - is frequently maintained in colorectal cancer (CRC), yet whether it actively contributes to tumour progression or metastatic competence remains unclear.

    Glandular architecture and malignant behaviour in colorectal cancer is regulated by the sialomucin Podocalyxin. · 2026 · DOI

  • SummaryPancreatic ductal adenocarcinoma (PDAC) exhibits marked molecular and microenvironmental heterogeneity, yet how tumor lineage states interact with the spatial immune microenvironment in advanced disease remains poorly understood.

    Spatial immune architecture and tumor lineage programs jointly shape clinical outcomes in advanced pancreatic ductal adenocarcinoma · 2026 · DOI

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits extensive molecular and microenvironmental heterogeneity, yet how tumor lineage states interact with spatial immune organization in advanced disease remains poorly understood.

    Spatial immune architecture and tumor lineage programs jointly shape clinical outcomes in advanced pancreatic ductal adenocarcinoma · 2026 · DOI

  • While mouse models and patient-derived organoids have advanced our understanding of lung cancer, key interactions within the tumor microenvironment (TME) remain poorly characterized.

    Ex Vivo Culture of Patient-Derived Primary, Metastatic, and Post-Mortem Lung Cancer Reveals Targetable States of EMT and Metabolic Plasticity · 2026 · DOI

  • Cancer-associated fibroblasts display extensive functional plasticity, yet the signaling mechanisms that stabilize distinct CAF states remain poorly understood.

    RAS-PI3K signaling promotes myofibroblastic CAF identity and restrains an immunomodulatory stromal program · 2026 · DOI

  • The conceptual framework of cancer MDR has defini- tively shifted from a static “drug efflux” model to a dynamic, multidimensional defense ecosystem. As syn- thesized herein, MDR is an emergent property of bidi- rectional tumor-TME crosstalk, integrating cell-intrinsic plasticity (e.g., CSC/DTP dynamics, metabolic-epigenetic rewiring) with extrinsic non-autonomous defenses (e.g., CAF-mediated desmoplasia, immune exclusion). Con- ventional therapeutic failure stems fundamentally from targeting isolated nodes within this network, overlook- ing the functional redundancy that facilitates tumor cell switching between transient adaptive tolerance and fixed genetic resistance along the “resistance continuum.” This dual-layered architecture evolves spatiotempo- rally: temporally via evolutionary subtypes (de novo to cross-resistance) securing clonal selection windows, and spatially through TME-facilitated horizontal propaga- tion of resistance (e.g., TNT-mediated mitochondrial transfer). Crucially, this adaptive reprogramming exposes actionable vulnerabilities. The reliance of DTPs on H4K20me3-mediated epigenetic silencing and the meta- bolic addiction of resistant clones to OXPHOS represent high-value therapeutic targets, necessitating a strategic pivot from “mono-targeted killing” to “multidimensional ecological remodeling.” Future strategies must converge on the integration of predictive and interventional technologies. Leverag- ing artificial intelligence, single-cell multi-omics, and longitudinal liquid biopsies will enable dynamic early- warning networks capable of prospecting resistance tra- jectories. These predictive capabilities must be paired with next-generation interventions—including spati- otemporally controlled nanomedicine, PROTACs, and immunotherapies targeting CSC/DTP-specific antigens (e.g., TROP2)—to synergistically dismantle the tumor’s intrinsic survival fortress and extrinsic physical-immune barriers. Realizing this vision requires establishing a closed- loop, adaptive clinical framework. This entails replacing static protocols with dynamic adjustments guided by Qiao et al. Molecular Biomedicine (2026) 7:98 Page 21 of 28 real-time molecular surveillance and adopting multidi- mensional endpoints that assess ecosystem remodeling (stromal reorganization, immune infiltration) alongside tumor regression. Although formidable challenges per- sist in navigating tumor heterogeneity, a systems-biol- ogy approach integrating mechanistic dissection with interdisciplinary innovation offers the most rational path to transform cancer from a lethal disease into a manageable chronic condition.

    Multidrug resistance in cancer: current understandings and future perspective · 2026 · DOI

  • However, the specific effects of combining rapamycin, an mTOR pathway inhibitor, with chemotherapeutic agents on CSC maintenance and overall tumorigenicity remain unclear.

    Rapamycin Targets Cancer Stem Cells to Decrease Cisplatin Resistance in a Head and Neck Cancer Mouse Xenograft Model · 2026 · DOI

  • Addressing the challenges posed by partial-EMT in OSCC will require coordinated efforts across several key areas. First, the integration of multi-omics data—including genomics, transcriptomics, proteomics, and epigenomics—will be essential for elucidating the molecular mechanisms and regulatory networks that drive partial-EMT. This systems-level approach can identify key regulators and signaling pathways, clarifying the complex relationship between EMT states and tumor progression. Advanced sequencing technologies, particularly single-cell and spatial platforms, enable detailed profiling of cellular phenotypes and interactions within the TME. These tools allow researchers to assess the stability of hybrid states and map their spatial context, offering insight into their biological and clinical relevance. Emerging spatial technologies, such as spatial transcriptomics and proteomics, offer practical solutions to current limitations in studying partial-EMT. By directly mapping gene and protein expression within tissue architecture, these tools can reveal the enrichment of partial-EMT programs at the invasive front and quantify their spatial associations with CAFs and immune cells. Spatial readouts can also distinguish early and late partial-EMT states by detecting coordinated expression of motility, matrix-interaction, and immune-exclusion modules—while preserving epithelial features.

    Partial-EMT in oral squamous cell carcinoma: molecular circuitry and clinical translation · 2026 · DOI

  • Anti-CSCs therapies poses a promising strategy in oncology due to their role in tumor initiation, therapy resistance, metastasis, and recurrence. Conventional treatments such as chemotherapy and radiotherapy primarily eliminate rapidly proliferating tumor cells but often fail to eliminate CSCs, especially the CSCs remaining in a quiescent state. As a result, surviving CSCs can repopulate the tumor after therapy (Stouras et al., 2023). Actually, there is no therapeutic tool that can find, identify and eliminate specifically CSCs, thus anti-CSCs strategies may target the stemness-, EMT- and metabolic plasticity-related signaling pathways (Milella et al., 2025). However, the features that characterize CSCs are also those that enable them to efficiently avoid current therapeutic tools. Heterogeneity and plasticity causes that the CSCs population is not homogeneous; different CSCs at the same tumor exhibit various gene expression profiles, metabolic interactions, and responses to therapy, making up overall tumor heterogeneity and therapy resistance. At the same tumor site, CSCs can synthetize various drug efflux transporters, DNA repair enzymes, and anti-apoptotic proteins, allowing them to survive anticancer therapy (Heppner et al., 1978). Another major challenge in anti-CSCs therapy is the metabolic of CSCs. Their metabolic plasticity allows them to survive under hostile conditions, evade metabolic inhibition and therapy-induced cell death. A key component of this flexibility is the capacity of CSCs to reprogram ATP production in response to metabolic targeting. To enable CSCs-targeted therapy, specific biomarkers are necessary, what remains a significant challenge for both CSCs research and therapeutic targeting. Several markers, including CD44, CD133, ALDH1 and EpCAM, have been widely used to detect and isolate CSCs populations across different cancer types. However, these markers are not universally expressed and are frequently shared with non-CSCs, raising concerns about their specificity and potential off-target effects (Lee et al., 2025a). The crucial therapeutic the process of CSCs target phenotypic change. target to is 6.1 Stem cells signaling pathways inhibitors and differentiation, survival. These One of the most frequently studied strategies is the inhibition of key signaling pathways responsible for maintaining CSCs stemness, especially embryonic stem cells markers, such as OCT-4, Nanog, Notch, and Wnt/β-catenin. These pathways regulate CSCs selfrenewal, strategies demonstrate high in vitro efficacy, but have no clinical translation (Lee et al., 2025a). During research of stem-like properties in lung cancer cells, Chen et al.

    Metabolic reprogramming and plasticity of cancer stem cells · 2026 · DOI

  • Nevertheless, whether exercise-induced alterations in ASC biology and function are necessary for exer- cise suppression of tumorigenesis in any tissue remains unknown. Although we propose a role for both cell-intrinsic and cell-extrinsic mechanisms, such as epigenetic and genomic altera- tions, immunity, and cell competition, these remain to be formally tested in rigorous experimental models.

    Stem cells as an essential mediator of the exercise–tumorigenesis link · 2026 · DOI

  • this platinum agent Cisplatin remains a cornerstone in the treatment of OSCC, yet the clinical efficacy of is frequently compromised by the emergence of drug resistance. The present review synthesizes current evidence to demonstrate that cisplatin resistance is not attributable to a single cause, but rather constitutes a complex, adaptive system. This system arises from the interplay between tumor cell-intrinsic alterations and extrinsic microenvironmental factors (Cheng et al., 2021), encompassing multiple interconnected dimensions such as genetic and epigenetic reprogramming, metabolic remodeling, evasion of regulated cell death, acquisition of stem-like properties, and dysregulation of the immune landscape. To address this multifaceted challenge, the research paradigm is shifting from purely mechanistic dissection toward the development of multi-target and multimodal intervention strategies. These strategies include the design of specific inhibitors against key resistance nodes, the use of nanotechnology for targeted drug delivery (Morgovan et al., 2025), the combination of cisplatin with immunotherapy to remodel the immunosuppressive microenvironment (Shibata et al., 2025), the exploitation of tumor-specific metabolic vulnerabilities (Zou et al., 2025). Collectively, such approaches represent an integrated therapeutic network targeting resistance across molecular, cellular, and microenvironmental scales. Ultimately, overcoming cisplatin resistance requires a fundamental evolution in therapeutic approach, driven by emerging technologies. Patient-derived organoids offer a physiologically relevant platform for in vitro drug testing and personalized strategy validation (Um et al., 2025). Single-cell multi-omics technologies decode tumor heterogeneity at un preceden ted resolu tion, p in point ing r are resist ant subpopulations and the crosstalk of these populations with the microenvironment (Doerfler et al., 2025). Artificial intelligence and machine learning integrate vast multi-scale datasets to build predictive models and accelerate biomarker and drug discovery (Liu et al., 2025). The synergy of these technologies—where singlecell analysis provides high-resolution maps, organoids enable functional testing (Han et al., 2025), and AI facilitates data integration and optimization—is propelling the field from population-level observations toward precision interventions guided by cellular atlases and individualized models. In summary, advancing against cisplatin resistance in OSCC necessitates a cohesive framework that links systematic mechanistic understanding, innovative therapeutic strategies, and cutting-edge translational technologies.

    Cisplatin resistance in oral squamous cell carcinoma: mechanisms, reversal strategies, and emerging technologies · 2026 · DOI

  • The paper references genomic characterization of 25,000 patients showing metastatic patterns but does not establish a mechanistic link between specific genomic mutations and the expression of organotropism-determining proteins (PTHrP, PDGF, VEGF). Integrated genomic-proteomic analyses are needed to correlate PTEN loss, STAT3 activation, and other molecular alterations with organ-specific metastatic tropism.

    An Overview of Metastatic Organotropism: Mechanisms and Emerging Therapeutic Targets · 2026 · DOI

  • The cross-talk between cancer-associated fibroblasts (CAFs) and organ-specific immune cells in the tumor microenvironment (TME) to establish pre-metastatic niches has not been systematically mapped. Future work should define the specific cytokine profiles (TNFα, RANKL, SEMA4D interactions with STING signaling) produced by CAFs in bone versus lung versus brain pre-metastatic niches.

    An Overview of Metastatic Organotropism: Mechanisms and Emerging Therapeutic Targets · 2026 · DOI

  • While the paper discusses circulating tumor cell (CTC) clustering and immune evasion mechanisms through scarcity of dormant disseminated tumor cells, there is a lack of temporal dynamics data comparing CTC clustering efficiency in organ-tropic versus non-tropic metastatic contexts. Studies should measure CTC aggregate formation kinetics in patients with organ-specific versus multi-organ metastatic disease.

    An Overview of Metastatic Organotropism: Mechanisms and Emerging Therapeutic Targets · 2026 · DOI

  • The mechanisms of paracellular and transcellular migration of metastatic cells through organ-specific endothelial barriers remain incompletely characterized. Research should quantitatively measure the roles of VCAM1, VAP-1, and VLA-4 integrin interactions in breaching the blood-brain barrier versus the pulmonary endothelium to determine organ-specific adhesion molecule expression patterns.

    An Overview of Metastatic Organotropism: Mechanisms and Emerging Therapeutic Targets · 2026 · DOI

  • The paper identifies organ-specific metastatic patterns but does not systematically characterize which tumor-derived secretory factors (TDSFs) and specific signaling cascades (PI3K/Akt, Wnt/β-catenin, TGF-β) are responsible for organotropism in individual cancer types. A comparative analysis of TDSF profiles across breast cancer subtypes and their correlation with pre-metastatic niche formation in distinct organs (lung, bone, brain) is needed.

    An Overview of Metastatic Organotropism: Mechanisms and Emerging Therapeutic Targets · 2026 · DOI

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84 open questions have been extracted from the limitations and future-work passages of 382 Cancer Cells and Metastasis 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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