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Open research questions in Cancer Immunotherapy and Biomarkers

592 unresolved questions extracted from the limitations and future-work sections of 1,211 Cancer Immunotherapy and Biomarkers papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The potential for on-target, off-tumor toxicity associated with PD-L1-targeting therapies. The need for a safe and effective method for expanding and maintaining PD-L1-specific T cells in vivo. The challenge of minimizing TCR mispairing and ensuring efficient knockout of the endogenous CD3-TCR complex.

    Engineering T cells with a novel PD-L1-specific TCR targeting immune and cancer cells · 2026 · DOI

  • further investigation of PD-L1-targeted TCR-based strategies, - exploration of in vivo vaccination strategy, - investigation of the potential synergy between immune checkpoint blockade and PDL101-TCR-T cells

    Engineering T cells with a novel PD-L1-specific TCR targeting immune and cancer cells · 2026 · DOI

  • investigating the effects of multi-target Traditional Chinese Medicine on the inflammatory substrate - studying the convergence of cryoablation-induced immunogenic cell death and multi-target Traditional Chinese Medicine

    Awakening antitumour immunity in the multimorbid host: a hypothesis coupling cryoablation-induced immunogenic cell death with multi-target Traditional Chinese Medicine · 2026 · DOI

  • The study was conducted in a specific population with resected NSCLC without sensitizing EGFR or ALK sequence variants, - The study did not evaluate the effect of adjuvant nivolumab in patients with other types of cancer, - The study was limited to patients who had completed planned adjuvant chemotherapy and/or radiotherapy

    Adjuvant Nivolumab vs Observation in Resected Non–Small Cell Lung Cancer · 2026 · DOI

  • A paradigm shift is required toward a multidimensional, dynamic biomarker platform to fully realize the clinical utility of Mtp53

    The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications · 2026 · DOI

  • The treatment of MSS/pMMR locally advanced rectal cancer is challenging due to its low tumor mutational burden and immunosuppressive microenvironment. The potential for immune-related adverse events. The need for careful patient selection and monitoring.

    Case Report: rapid clinical complete response to Iparomlimab and Tuvonralimab combined with radiotherapy and chemotherapy in a patient with MSS/pMMR locally advanced rectal cancer · 2026 · DOI

  • The lack of effective treatment for MSS/pMMR locally advanced rectal cancer. The need for a safer and more efficient treatment paradigm. The potential of immunotherapy in treating MSS/pMMR locally advanced rectal cancer.

    Case Report: rapid clinical complete response to Iparomlimab and Tuvonralimab combined with radiotherapy and chemotherapy in a patient with MSS/pMMR locally advanced rectal cancer · 2026 · DOI

  • The lack of a standardized definition for HPD and its predictive biomarkers. The variability in study design and data quality. The potential for publication bias and heterogeneity across studies.

    Sex and risk of hyperprogressive disease in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis · 2026 · DOI

  • The study only included retrospective studies. The lack of a standardized definition for HPD and its predictive biomarkers remains a challenge. The analysis revealed low heterogeneity among the studies, but sensitivity analysis was still conducted.

    Sex and risk of hyperprogressive disease in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis · 2026 · DOI

  • Further studies are needed to confirm the findings, - Research should focus on optimizing risk-benefit assessment of ICI-based therapies in the elderly population, - Studies should investigate the potential predictive markers for improved treatment response

    Immune-related adverse events and clinical outcomes in advanced non-small cell lung cancer: does more toxicity predict better outcomes? · 2026 · DOI

  • determine whether T2DM is associated with a reproducible increase in hepatic GZMK + CD8 + T cells before and during HCC development, - compare GZMK + CD8 + T cells across a staged liver disease spectrum, - control for potential confounders in human cohorts

    Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review · 2026 · DOI

  • The effects of metabolic dysfunction on hepatic antitumor immunity remain incompletely defined. Direct evidence that type 2 diabetes induces GZMK+ CD8+ T cells in the liver is limited. The functional significance of GZMK+ CD8+ T cells in HCC is highly context-dependent.

    Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review · 2026 · DOI

  • Combination approaches integrating immune checkpoint blockade with metabolic modulation, epigenetic therapy, or personalized neoantigen vaccination may help restore antitumor immunity and overcome resistant tumor subclones. Optimal treatment timing, patient stratification, and control of immune-related toxicity remain major challenges.

    Cancer immunoediting in the melanoma tumor microenvironment: from immune elimination to therapeutic resistance · 2026 · DOI

  • Further studies are needed to characterize tislelizumab-associated SAI, - Longitudinal endocrine assessment is necessary to understand the effects of ICIs on the pituitary-adrenal axis, - Research into the mechanisms of ICI-associated SAI is required, - Studies should investigate the incidence and prevalence of SAI in patients treated with tislelizumab

    Case Report: Tislelizumab-associated secondary adrenal insufficiency in a patient with lung squamous cell carcinoma · 2026 · DOI

  • Tislelizumab-associated secondary adrenal insufficiency remains insufficiently characterized. There is a lack of understanding of how and when tislelizumab-associated secondary adrenal insufficiency is recognized. The mechanism of ICI-associated secondary adrenal insufficiency is not fully understood.

    Case Report: Tislelizumab-associated secondary adrenal insufficiency in a patient with lung squamous cell carcinoma · 2026 · DOI

  • Retrospective nature of the study, - Limited to patients with diverse malignancies undergoing PD-1 inhibitor therapy, - No mention of long-term follow-up or potential late effects

    Predictive value of pre-existing thyroid autoantibodies for PD-1 inhibitor-induced hypothyroidism: a retrospective cohort study · 2026 · DOI

  • Investigation of the underlying mechanisms of ICI-induced hypothyroidism, - Development of predictive models incorporating multiple risk factors, - Study of the clinical implications of hypothyroidism in patients receiving PD-1 inhibitors

    Predictive value of pre-existing thyroid autoantibodies for PD-1 inhibitor-induced hypothyroidism: a retrospective cohort study · 2026 · DOI

  • The current mechanistic model of TLS development is incomplete. The role of non-immune components in TLS formation is not fully understood. The contribution of extracellular matrix remodeling and tumor metabolism to TLS neogenesis and maturation is not well characterized.

    Non-immune regulation of tertiary lymphoid structures in cancer · 2026 · DOI

  • Non-immune stromal, vascular, and matrix components play coordinated and necessary roles in TLS formation. CAFs establish stromal networks and chemokine gradients that organize immune cells, either supporting or suppressing TLS formation. HEVs regulate lymphocyte access through specialized adhesion molecules, while the ECM provides the biochemical and biomechanical frame- work that supports TLS structure and function. Indeed, successful TLS formation depends on coordinated interactions between immune and non-immune components of the TME. Evolving spatial technologies will help to define the mechanisms through which the TME regulates TLS formation, characterize the trajectory of TLS maturation, and clarify the functional importance of TLS localization within the tumor. These advances may lead to the discovery of novel targets to improve ICI efficacy and cancer patient outcomes.

    Non-immune regulation of tertiary lymphoid structures in cancer · 2026 · DOI

  • The impact of time-of-day administration on the prognosis of advanced gastric cancer patients is unclear. Prior studies have focused on other types of cancer, and the optimal cutoff time for distinguishing prognostic differences is unknown. A risk stratification model for precision immunotherapy in gastric cancer is needed.

    Early time-of-day infusion of PD-1 inhibitor improves prognosis in advanced gastric cancer: a multicenter real-world study · 2026 · DOI

  • The genomic complexity and highly heterogenous nature of oesophageal adenocarcinoma make it challenging to develop a comprehensive understanding of the immune microenvironment. The lack of reliable genomic biomarkers for response and survival in oesophageal adenocarcinoma is a significant challenge. The study had to overcome the challenge of identifying putative neoantigens from two independent cohorts.

    The neoantigen and associated tumour microenvironment in long-term survivors with oesophageal adenocarcinoma · 2026 · DOI

  • The study had a limited sample size of 149 OAC patients from The Cancer Evolution Biobank and GI Cancer Trials DOCTOR trial. The study only analysed treatment-naïve primary tumour and blood samples. The study did not investigate the effect of different treatments on neoantigen expression and immune response.

    The neoantigen and associated tumour microenvironment in long-term survivors with oesophageal adenocarcinoma · 2026 · DOI

  • The study is a stage 1 trial and the results may not be generalizable to the entire population, - The sample size is relatively small, - The study only evaluated gotistobart in patients with metastatic sqNSCLC, - The follow-up period was limited to a median of 14.5 months

    Gotistobart or docetaxel in metastatic squamous non-small cell lung cancer: stage 1 of the randomized phase 3 PRESERVE-003 trial · 2026 · DOI

  • Limited treatment options for patients with metastatic squamous non-small cell lung cancer who progressed on programmed cell death protein/programmed death ligand 1 inhibitor/platinum-based chemotherapy, - Need for novel therapies that can provide clinically meaningful benefits in this patient population

    Gotistobart or docetaxel in metastatic squamous non-small cell lung cancer: stage 1 of the randomized phase 3 PRESERVE-003 trial · 2026 · DOI

  • this study was not designed to assess efficacy, - the study had a small sample size, - further phenotypic resolution of B cell subsets was limited by tissue availability and marker constraints

    Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial · 2026 · DOI

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592 open questions have been extracted from the limitations and future-work passages of 1,211 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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