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Open research questions in Immunotherapy and Immune Responses

32 unresolved questions extracted from the limitations and future-work sections of 233 Immunotherapy and Immune Responses papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Aberrant glycosylation is a hallmark of cancer that extends to TDEVs, yet how tumour-associated glycans within EV cargo modulate cell function remains poorly understood.

    Sialyl-Tn-positive tumour-derived extracellular vesicles impair dendritic cell function via horizontal transfer of glycans · 2026 · DOI

  • As mechanically fractionating tumors with BH may potentiate T cell‐mediated anti‐tumor responses, we addressed gaps in knowledge regarding the impact BH has on antigen‐presenting cell (APC) presence in the tumor microenvironment (TME), antigen acquisition, and conventional dendritic cell (cDC) activation states in settings where BH does or does not induce a primary tumor growth response.

    Immediate Growth Control in Response to Boiling Histotripsy is Prognostic for Intratumoral Immune Activation · 2026 · DOI

  • However, their early molecular and functional effects on CD8+ T cells remain incompletely characterized, and whether engineering activated DC-derived EVs with immunomodulatory cargo can fine-tune these responses remains largely unexplored.

    Extracellular Vesicles Derived from Activated Dendritic Cells Loaded with Curcumin Promote Early Activation-associated Functional and Molecular Reprogramming of Primary CD8+ T Cells · 2026 · DOI

  • Yet their origins and differentiation states remain poorly defined, limiting both the interpretation of residency-based tumor-infiltrating lymphocyte (TIL) phenotyping and efforts to rationally harness these TRM-like cells.

    Circulating and brain-resident memory CD8+ T cells seed distinct bystander TRM-like populations in glioblastoma · 2026 · DOI

  • Although extracellular vesicles (EVs) are increasingly explored as cancer biomarkers, how distinct EV subpopulations reflect dynamic tumor states induced by immune pressure remains insufficiently understood.

    Distinct melanoma EV subpopulations reflect immune- and stress-induced tumor states · 2026 · DOI

  • Generative AI statement This Research Topic argues for a pragmatic shift in immune- related biomarker science. Focusing on breast and skin cancers, malignancies with so different immunophenotypes - in terms of both extracellular (immune infiltrate rates, tumor microenviron- ment status, etc.) and intracellular (quantitative and qualitative molecular alterations such as TMB and pathogenetic mutations, respectively) features, is precisely in the direction of overcoming the use of conventional markers for the assessment of immune-respon- siveness or -resistance of tumors. In breast cancer, the most informative signals are likely to emerge from the integration of tumor-intrinsic programs, cytokine biology, inflammation, imaging and computational pathology. In skin cancer, biomarker develop- immunometabolism, ment is converging on stress adaptation, retroelement biology, extracellular vesicles, transcriptomic archi- tecture, toxicity prediction and response durability. Across both fields, the goal is no longer to catalog plausible markers, but to build The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

    Editorial: Immune-related biomarkers in skin and breast cancer: innovations in immunological diagnostics and therapies · 2026 · DOI

  • Further research is on for current inhibition, however an area of rapid progress in mRNAbased vaccines are new inhibitors aimed at improving therapeutic efficacy. Personalized strategy and delivery technologies coupled with integrated computational biology will probably position mRNA vaccines in an even larger role for melanoma and other cancers.[10,11] 9.1 AI-Driven Neoantigen Prediction The application of AI and machine learning for neoantigen prediction pipelines is becoming routine, enabling the faster and more accurate design or personalized mRNA vaccines. The approaches function by screening genomic data from tumors to find neoantigens that induce strong T-cell responses termed highly immunogenic. In addition, AI-based algorithms can help predict peptide–MHC binding affinity, antigen processing and the immunogenicity of genotyped patients to enhance vaccine efficacy. These technologies significantly shorten the time frame for vaccine development and enable more focused targeting at tumor-specific mutations. 9.2 Combination Immunotherapies Combination strategies with mRNA vaccines and various other immunotherapies will likely be found in future therapeutics to pursue synergy. This introduction features combinations with immune checkpoint antibodies, adoptive T-cell therapeutics and cytokine-based therapeutics that have informed strategies to enhance anti-tumor responses. www.wjpr.net │ Vol 15, Issue 12, 2026. │ ISO 9001: 2015 Certified Journal │ 38 Saher et al. World Journal of Pharmaceutical Research Such combinations are meant to overcome immune resistance mechanisms and enhance response durability. D') Combining checkpoint blockade with mRNA vaccines, for instance, may enhance T-cell activation and microenvironment. 9.3 Improved Delivery Systems reduce immune suppression in the tumor This semi-In vivo delivery could reaching the therapeutic mRNA vaccines potential. New delivery systems (i.e. lipid nanoparticles, polymeric carriers, hybrid nanomaterials) are designed for enhanced stability, specificity and cellular desorption.[11,12] Delivery to dendric cell specifically or improved endosomal escape mechanism would dramatically improve the efficiency of vaccine.[46-48] In addition, the development of thermostable formulations now being pursued will address existing storage and distribution challenges.

    MRNA-BASED VACCINES IN MELANOMA THERAPY: MECHANISMS, ADVANCES, AND CLINICAL PERSPECTIVES · 2026 · DOI

  • Together with earlier N-803 plus nivolumab data in NSCLC (34), this combination experience provides direct clinical precedent for the broader staged combination logic proposed here, even though the optimal sequence remains to be defined.

    Beyond priming: a sequential, feedback-guided adjuvant framework for therapeutic cancer peptide vaccines in immunologically cold tumors · 2026 · DOI

  • A combination of video rate intravital and high-resolution microscopy will be needed to discern the precise steps during transendothelial migration where CCR7-CCL19 and EBI2-7α,25-HC act. While our finding that LCs contribute to lymphocyte-recruiting oxysterol production is supported by expression, BM chimera, and cell ablation studies, a more definitive test will involve conditional Ch25h deletion in LCs. While some LCs were observed to be adjacent to HEVs, most were T-zone localized, and we infer that oxysterols travel several cell diameters to engage HEV-associated lymphocytes. As future work investigates EBI2 action in LNs draining tissues other than skin, it will be of interest to assess oxysterol production by further myeloid cell types. STAR★METHODS RESOURCE AVAILABILITY Lead contact—Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Jason G. Cyster ([email protected]). Materials availability—This study did not generate new, unique reagents.

    Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes · 2024 · DOI

  • These findings lay the groundwork for further investigation of this non-canonical T-cell subset, with the ultimate goal of improving the efficacy of T-cell-based cancer immunotherapies.

    Investigating Cytotoxic Function in CD4+ T-cells for Cancer Immunotherapy 2260082 · 2026 · DOI

  • Tumour-derived extracellular vesicles (TDEVs) are emerging regulators of immune escape, however the role of glycan-mediated mechanisms remains elusive.

    Sialyl-Tn-positive tumour-derived extracellular vesicles impair dendritic cell function via horizontal transfer of glycans · 2026 · DOI

  • Combination of ADC with immunotherapy is a promising strategy but mechanisms and effective application remain to be determined.

    Mechanisms regulating combination effect of antibody-drug conjugates and cancer immunotherapy · 2026 · DOI

  • Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear.

    Dendritic cells control tertiary lymphoid structure development and maintenance in cancer · 2026 · DOI

  • However, high-plex, spatially resolved maps that couple injection site signals with transcriptomic programs in draining lymph nodes over time are still lacking.

    Spatial transcriptomic mapping of early immune responses to an adjuvanted recombinant hemagglutinin vaccine · 2026 · DOI

  • We speculate that it is likely not the primary interacting protein of KC-1 and thus will not pursue further investigation into it.

    Discovery of KC-1: a novel porcine dendritic cell-targeting peptide with potential applications in swine vaccine design · 2026 · DOI

  • ABSTRACT The clinical translation of cancer vaccines remains limited by the inability to effectively coordinate innate and adaptive immunity.

    A Glucose Metabolism‐Modulatory Nanobiohybrid Vaccine Platform Promotes Anti‐Tumor Immunity by Orchestrating Autophagy‐Dependent Cross‐Presentation and H <sub>2</sub> S‐Enhanced NLRP3 Inflammasome Signaling · 2026 · DOI

  • Further study on the potential for ADCs or CAR-T cell therapies to treat DICER1-related conditions is needed.

    Abstract A018: Identifying potential cell-surface targets for therapeutic treatment of <i>DICER1</i> -related cancers · 2026 · DOI

  • Adoptive T-cell therapies rely on the identification and expansion of rare tumor-reactive T cells, yet current enrichment strategies are limited by the low abundance of these cells and complexity of their functional enrichment.

    Hydrodynamic shear enables enrichment of functional tumor antigen-reactive T cells · 2026 · DOI

  • However, to what extent post-transplant immune recovery reflects restoration of pre-treatment state versus selective remodeling remains incompletely understood.

    Lineage-Specific Immune Remodeling Following Autologous Hematopoietic Stem Cell Transplantation in Relapsing-Remitting Multiple Sclerosis · 2026 · DOI

  • Since recent studies have shown that many lncRNAs contain non-canonical open reading frames (ncORFs) that are translated into small proteins, or microproteins, there could be a large class of non-canonical cancer-germline antigens (ncCGAs) that remains to be discovered.

    Identification of a large class of cancer-germline microproteins as a source of immunotherapeutic targets · 2026 · DOI

  • However, the functional properties of colonist-induced T cells are not well defined, limiting our ability to understand anticommensal immunity and harness it therapeutically.

    Engineered skin bacteria induce antitumor T cell responses against melanoma · 2023 · DOI

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32 open questions have been extracted from the limitations and future-work passages of 233 Immunotherapy and Immune Responses 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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