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Open research questions in Cancer Immunotherapy and Biomarkers

142 unresolved questions extracted from the limitations and future-work sections of 642 Cancer Immunotherapy and Biomarkers papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • I e l b a T Although several predictive biomarkers, such as PD‑L1 expression, tumor mutation burden, microsatellite instability, microbial diversity, hypoxia, interferon‑γ and extracellular matrix, are utilized to predict response to immunotherapy, the data regarding biomarkers for irAEs are scarce (10,11).

    Immune‑mediated liver injury caused by checkpoint inhibitors: A case series and review of the literature · 2026 · DOI

  • In addition, while strong associations are identified, causal relationships between GIMAP7 expression, LTB signaling, and T cell function remain to be established. There are several limitations of this study that need to be acknowledged.

    Single-cell transcriptomic analysis identifies a tumor-enriched GIMAP7⁺ CD4⁺ naïve T cell population with a unique immunoregulatory state in lung adenocarcinoma · 2026 · DOI

  • Although the introduction of immune checkpoint inhibitors, such as anti-PD-1, has improved patient survival, treatment responses remain heterogeneous, and the complete mechanisms of action are not yet fully understood.

    Exploring the Role of Natural Anti-PD-L1 antibodies in Shaping the Anti-Tumor Immune Response to Neoadjuvant Chemo-Immunotherapy in NSCLC 2308226 · 2026 · DOI

  • Abstract Introduction Lysophosphatidylcholine (LPC) is a bioactive lipid with emerging immunomodulatory properties, but its potential as an adjuvant to immune checkpoint blockade (ICB) is poorly understood.

    Lysophosphatidylcholine (LPC 18:2) Reprograms the Tumor Immune Microenvironment to Potentiate Immune Checkpoint Blockade 2309882 · 2026 · DOI

  • Abstract Introduction Conventional dendritic cells (cDCs) are essential for sustaining CD8+ T cell-mediated tumor immunity, yet the developmental mechanisms controlling their homeostasis remain unclear.

    The Ubiquitin Ligase Marchf1 Controls cDC Development to Sustain CD8+ T Cell Antitumor Immunity and Response Checkpoint Blockade 2259196 · 2026 · DOI

  • Background Thyroid dysfunction is among the most frequent endocrine immune-related adverse events (irAEs) during PD-1/PD-L1 blockade, but whether baseline thyroid function and treatment-emergent thyroid dysfunction (TeTD) predict pathological response and survival after neoadjuvant immunochemotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma (LAGC/GEJC) remains unclear.

    Baseline thyroid function and treatment-emergent thyroid dysfunction predict pathological response and survival after neoadjuvant PD-1 inhibitor plus platinum-based chemotherapy in locally advanced gastric and gastroesophageal junction adenocarcinoma: a multicenter cohort study · 2026 · DOI

  • Immune checkpoint inhibitors (ICIs) may be effective in this population, although evidence remains limited because PLWH have often been excluded from trials.

    Immune checkpoint inhibitors in people living with HIV and cancer: a Kaplan–Meier-derived individual patient data meta-analysis · 2026 · DOI

  • Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions.

    Effectiveness and Safety of Immunotherapy in Advanced NSCLC with Pericardial Effusions: A Global Retrospective Multicenter Study · 2026 · DOI

  • While the RT-TLS relationship provides a framework for assessing local therapy beyond tumor-cell killing, the field remains at an early stage of validation. RT can alter antigen release, innate immune signaling, lymphocyte trafficking, vascular states, and lymph-node function. TLSs are clinically relevant immune-organizing niches, yet it remains unresolved whether RT can deliberately preserve or generate functional TLSs. The evidence reviewed here supports a state-, dose-, space- and time-dependent model. The strongest evidence concerns RT-induced ICD, cGAS-STING/type I interferon signaling, lymphocyte depletion, and TDLN effects. Direct TLS-specific evidence is more limited and context-dependent, including selected models of low- dose RT-associated TLS-like organization and clinical tissue studies showing disruption of mature TLSs after certain treatment regimens. Several technical bottlenecks need to be addressed before TLS-guided RT can be translated. Current TLS assessment still relies mainly on tissue-based pathology, multiplex immunofluorescence and spatial profiling, which are invasive, sampling- dependent and difficult to repeat dynamically. TLS scoring is not yet standardized across tumor types, and noninvasive methods such as radiomics or circulating biomarkers require external validation against spatial histology. Practical countermeasures include harmonized TLS scoring criteria, paired pre- and post-treatment biopsies when feasible, integration of tumor tissue, TDLNs, peripheral blood and imaging data and prespecified TLS endpoints in RT- immunotherapy trials. These endpoints should distinguish TLS density from maturity, germinal-center activity, HEV/FDC/FRC integrity, spatial localization, and suppressive stromal or myeloid barriers. ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT Future trials should therefore treat TLSs first as stratification biomarkers and exploratory endpoints. Paired assessments of TLS density and maturity, HEV and FDC/FRC integrity, DLN function, TCR/BCR repertoires, circulating CXCL13 and imaging or digital pathology predictors are needed to distinguish functional immune organization from transient inflammation. Contemporary RT-immunotherapy studies in nasopharyngeal carcinoma, esophageal adenocarcinoma, cisplatin-ineligible head and neck cancer, Merkel cell carcinoma, and cold NSCLC provide clinical design contexts for future RT-TLS trials [216–220]. Future RT-TLS protocols should explicitly add paired tissue, blood and, where feasible, nodal immune monitoring rather than assuming that these elements are already present across all template studies. Therapeutically, the near-term priority is to test stratified combinations without assuming that TLS biology is clinically controllable. RT may provide antigen release and innate immune activation; STING or LTβR agonists may amplify organogenesis- related signals in preclinical settings; ICB may relieve adaptive suppression; and vascular normalization or stromal reprogramming may improve lymphocyte access and residence. Overall, TLS-oriented RT remains a promising research hypothesis rather than an established clinical strategy. The central challenge is to determine whether RT can reproducibly preserve or promote functional mature TLSs, in which tumor types and under which RT–immunotherapy conditions, and whether such effects translate into durable clinical benefit.

    Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy · 2026 · DOI

  • Author contributions A growing body of literature identifies gastric cancer as a paradigmatic model of Treg-mediated immune evasion. Crucially, the equilibrium between immunosuppressive stable Tregs and proinflammatory fragile subsets,rather than the sheer abundance of total Tregs, appears to dictate the host immune landscape and therapeutic outcomes. As a pivotal regulator of this dynamic, H. pylori infection exhibits stage-specific duality: acute infection trig- gers proinflammatory signaling that induces Treg fragility, whereas chronic persistence fosters Treg stabilization. This dichotomy delineates a distinct therapeutic window for upstream etiologi- cal targeting. The unified Treg bimodal model proposed in this review establishes a testable mechanistic framework for understanding Treg heterogeneity and plasticity in gastric cancer. Both the Treg- SF score and the three combination regimens derived from this model are hypothesis-generating concepts. Integrating Treg func- tional status, H. pylori infection status, and CD8+ T cell density, the Treg-SF score is expected to predict immunotherapy response more accurately than existing biomarkers, including PD-L1 CPS, MSI-H, and TMB. The three combinatorial strategies target Treg plasticity from three complementary dimensions: upstream etiological inter- vention, selective depletion of stable Tregs, and pharmacological induction of Treg fragility. Their shared goal is to reverse tumor immunosuppression by reducing the S/F ratio, instead of non- specifically eliminating all Treg populations. All these hypotheses require rigorous preclinical validation and prospective clinical trials. Priority directions for future research include: (1) prospective clinical validation of the Treg-SF score; (2) functional characteri- zation of gastric cancer-specific fragile-like Tregs; (3) development of tumor-specific Treg modulators. Finally, as a highly plastic immunomodulatory subset, Tregs possess therapeutic potential far beyond tumor immunology. The bimodal model and fragility-inducing strategy proposed herein can be extrapolated in the opposite direction to autoimmune diseases, namely, restoring immune tolerance by stabilizing Treg phenotypes and inhibiting fragility. Research between the two fields can inducing Treg fragility to break mutually inspire each other: immune tolerance in tumor immunity, versus maintaining Treg stability to restore tolerance in autoimmunity. Their molecular mechanisms mirror each other, and therapeutic strategies can be mutually referenced. Systematically investigating Treg plasticity under a shared framework covering oncology and autoimmunity may broaden the landscape of precision immunotherapy. PZ: Writing – original draft, Writing – review & editing. DW: Writing – review & editing. HZ: Writing – review & editing. FZ: Writing – review & editing. ZL: Writing – review & editing. HX: Writing – review & editing.

    Targeting regulatory T cell plasticity in gastric cancer: a unified bimodal model and precision immunotherapy paradigm: a hypothesis-generating review · 2026 · DOI

  • The clinical evidence base for ImmunoPET is uneven across histologies. Thoracic oncology has generated the largest and most mature dataset, with several completed Phase I/II trials now reporting predictive correlates (116, 117). Genitourinary and gas- trointestinal cancers are catching up through targeted CAIX, HER2, and PD-L1 imaging programs (118–120). Hematological malignan- cies have benefited from the particularly favorable pharmacokinet- ics of radiolabeled anti-CD20 and anti-CD38 agents in the vascular compartment (121). Neuro-oncology remains the most challenging context, where the blood–brain barrier selectively excludes the large scaffolds that dominate the current clinical portfolio (122–124).

    Emerging ImmunoPET probes for precision cancer immunotherapy: molecular targets and translational applications · 2026 · DOI

  • How this study might affect research, practice or policyThese findings support further investigation of CHIP as a genotype-specific biomarker of melanoma biology that has the potential to refine risk stratification for patients with advanced melanoma.

    Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival · 2026 · DOI

  • These findings support further investigation of genotype-specific CHIP profiling as a potential biomarker for melanoma risk stratification and immunotherapy outcomes.

    Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival · 2026 · DOI

  • Prior studies have suggested that CHIP may influence immune function and response to immune checkpoint inhibitors, but the clinical relevance of CHIP in melanoma, particularly by CHIP genotype, clone size, and tumor BRAF genotype, remains incompletely defined.

    Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival · 2026 · DOI

  • BackgroundThe clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) in melanoma remains incompletely defined, particularly with respect to CHIP genotype, clone size, and somatic mutations (e.

    Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival · 2026 · DOI

  • Background Currently, immune checkpoint inhibitors (ICIs) have become a mainstay in treating advanced esophageal cancer (EC), yet the predictive significance of routinely collected clinicopathological characteristics for overall survival (OS) remains uncertain.

    Associations of PD-L1 expression status, tumor histology and patient ethnic background with immunotherapy outcomes in patients with advanced esophageal cancer · 2026 · DOI

  • Despite these breakthroughs, translating this encouraging short- term pathological response advantage into definitive long-term sur- vival benefits and widespread, safe clinical practice remains fraught with critical challenges and unanswered questions. First, the long-term translation of efficacy requires urgent validation. Large-scale Phase III randomized controlled trials with extended follow-up data are ur- gently needed to confirm whether the improved pCR rate can be robustly translated into ultimate improvements in DFS and OS.This is the fundamental basis for establishing the new strategy as standard treatment. Second, standardization and optimization of treatment regimens require refinement. This encompasses determining the optimal duration of immunotherapy, clarifying precise dosing and sequencing when combined with different chemoradiotherapy mo- dalities (e.g., SCRT vs. LCRT), and establishing standardized manage- ment pathways for rare but severe irAEs. Furthermore, achieving true personalized precision medicine necessitates deepening our under- standing of the mechanisms underlying immune combination thera- pies. Future basic and translational research urgently requires moving beyond comparative clinical endpoints to deeply explore how different RT modalities and immunotherapy combinations differentially re- model the tumor immune microenvironment. This includes investi- gating their effects on T-cell receptor repertoire diversity, myeloid cell subset function, and the formation of tertiary lymphoid structures. Simultaneously, identifying novel biomarkers predictive of treatment response, such as peripheral immune cell dynamics, specific cytokine profiles, intratumoral B-cell characteristics, or novel serum markers, and integrating them with genomic features to construct multidimen- sional predictive models will be key to achieving precise patient selection. Furthermore, dynamic monitoring using ctDNA combined with immune-specific markers not only enables more precise assess- ment of pathological response but also reveals real-time tumor immune evolution under therapeutic pressure. This provides a scien- tific basis for decision-making regarding W&W strategies and subse- quent treatment adjustments. Looking ahead, LARC therapy will inevitably enter a new phase characterized by greater personalization, precision, and humanization. This demands that clinicians and researchers move beyond merely stacking treatment modalities. Instead, they must design treatment sequences that maximize the body’s inherent anti-cancer potential, grounded in a deep understanding of the tumor immune ecosystem. Through rigorous clinical validation, close interdisciplinary collabora- tion, and unwavering commitment to our core value of patient- centered care, we aim to translate this scientific breakthrough into tangible, long-term benefits for every patient. This means achieving disease eradication while preserving dignity, function, and quality of life to the greatest extent possible, ultimately ushering gastrointestinal cancer treatment into a new era where cure and quality coexist.

    Synergistic neoadjuvant radioimmunotherapy in locally advanced rectal cancer: mechanisms of pathologic response and the shift toward organ preservation · 2026 · DOI

  • FMT trials demonstrate that responder-derived microbiota outper- forms healthy donor material, suggesting that the ideal transplant is not a restored normal flora but a functionally vetted consortium primed by prior ICI exposure; however, the specific microbial features required remain incompletely characterized.

    Navigating the gut–metabolite–immune axis: enhancing efficacy and mitigating toxicity of immune checkpoint inhibitors · 2026 · DOI

  • Abstract Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) respond poorly to anti-PD-1 monotherapy, but the underlying immune resistance remains incompletely defined.

    Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8+ T cell responses and promoting tertiary lymphoid structure formation · 2026 · DOI

  • NAT could thus be particularly effective in cold, myeloid-rich tumors that are largely unresponsive to conventional immunotherapies such as checkpoint blockade, enacting these anti-tumoral effects through similar and different mechanisms; however, this has not been tested.

    Single-cell multi-omics analysis reveals heterogeneity and plasticity of neutrophil states in response to immunotherapies · 2026 · DOI

  • Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined.

    Combination Immunotherapy Enhances Serial Radiofrequency Ablation Induced Systemic Antitumor Immunity in Pancreatic Cancer · 2026 · DOI

  • The spatial arrangement of immune cells in the tumor microenvironment (TME) varies widely, from dispersed to clustered and tumor excluded to infiltrating.

    Spatial statistics for identifying and scoring immune clusters in high-plex profiles of primary prostate cancer · 2026 · DOI

  • Although the precise ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT mechanisms linking reduced BCR diversity and expansion of dominant IgG clones to irAE development remain unclear, these findings provide a basis for early prediction of irAEs during treatment.

    Peripheral B-cell receptor repertoire predicts immune-related adverse events following immune checkpoint inhibitor therapy in advanced renal cell carcinoma · 2026 · DOI

  • The consistent upregulation of LSM12 at both mRNA (TIMER2, GEPIA2) and protein (CPTAC, HPA) lev- els across 18 tumor types establishes a broad oncogenic expression signature for this previously understudied protein.

    Integrated pan-cancer multi-omics profiling and experimental validation identify LSM12 as a prognostic biomarker and candidate therapeutic target in human cancers · 2026 · DOI

  • Additionally, the relatively small sample size may limit the statis- tical power of the survival analyses, and direct evidence supporting the role of the HIF-1a/PD-L1 axis in LATO’s mechanism remains lacking. Future studies employing orthotopic or spontaneous HCC models, with larger cohort sizes, expanded detection metrics, and optimized dosing regimens of LATO, are warranted to validate these findings and further evaluate the impact of this combination strategy on distant metastasis and immune modulation.

    Mechanism of liposome arsenic trioxide regulating tumor microenvironment and sensitizing tumor immune response after radiofrequency ablation · 2026 · DOI

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142 open questions have been extracted from the limitations and future-work passages of 642 Cancer Immunotherapy and Biomarkers 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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