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Molecular Research for Cancer Immunotherapy
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Molecular Research for Cancer Immunotherapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 October 2025) | Viewed by 13940

Special Issue Editor

Dr. Mariana Malvicini

E-Mail Website
Guest Editor
Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
Interests: immune cells in tumor microenvironment; lung cancer; head and neck squamous cell carcinoma; oral cancer; extracellular matrix; chemoimmunotherapy; immunotherapy; immune checkpoints inhibitors; cancer stem cells; immune evasion; immune related-resistance mechanisms

Special Issue Information

Dear Colleagues,

Given the significant advances in quality of life and survival for patients with advanced tumors that have come with immunotherapy becoming a therapy of choice, this Special Issue attempts to explore the latest findings in molecular research in cancer immunotherapy. Focusing on deepening our understanding of the molecular complexities that govern the interaction between tumors and immune cells, we invite contributions investigating the role of molecular pathways in tumor immune evasion, characterizing the immune tumor microenvironment, identifying new biomarkers, and highlighting innovative molecular-based immunotherapeutic approaches, such as immune checkpoint inhibitors, CAR-T cell therapy, and cancer vaccines. This Special Issue aims to allow for more the establishment of effective cancer immunotherapies.

Dr. Mariana Malvicini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer immunotherapy
  • tumor immune microenvironment
  • tumor immune evasion
  • adoptive cell therapies
  • immune checkpoint inhibitors
  • neoantigen-based vaccines
  • chemoimmunoresistance
  • primary immunoresistance
  • adaptive immunoresistance
  • tumor associated-macrophages
  • tumor-immune crosstalk

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

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Research

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22 pages, 14831 KB  
Article
4-Methylumbelliferone Modulates CAIX to Mitigate Hypoxia-Driven Dysregulation and Enhance PD-1 Immunotherapy in Lung Cancer
by Mariel Fusco, Carlos Rafael Picón, Marco Aurelio Diaz, Juan Bayo, Paula Constanza Arriola Benitez, Flavia Piccioni, Noelia Gómez, Mara Stinco, Javier Martínez Martinez, José Nicolás Minatta, Ricardo Amorín, Martina Villar, Valentina Sole, Ignacio Cassol, Mauricio De Marzi, Manglio Miguel Rizzo, María Florencia Mercogliano and Mariana Malvicini
Int. J. Mol. Sci. 2025, 26(21), 10427; https://doi.org/10.3390/ijms262110427 - 27 Oct 2025
Cited by 2 | Viewed by 2051
Abstract
Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with [...] Read more.
Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer. Full article
(This article belongs to the Special Issue Molecular Research for Cancer Immunotherapy)
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Review

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31 pages, 2599 KB  
Review
Emerging CRISPR Approaches for Countering Immune Evasion: Insight from Recent Studies
by Sadam Abubakar, Latifat Abdulsalam, Lamin Fatty, Rimsha Kanwal, Muhammad Naeem and Irshad Ahmad
Int. J. Mol. Sci. 2026, 27(7), 2930; https://doi.org/10.3390/ijms27072930 - 24 Mar 2026
Cited by 1 | Viewed by 1008
Abstract
Cancer immunotherapy has recently become an essential approach for treating cancer, showing considerable promise as a substitute for surgery, radiation therapy, and conventional chemotherapy. It primarily aims to boost the host’s natural defense system to combat cancer malignancies by utilizing components of immune [...] Read more.
Cancer immunotherapy has recently become an essential approach for treating cancer, showing considerable promise as a substitute for surgery, radiation therapy, and conventional chemotherapy. It primarily aims to boost the host’s natural defense system to combat cancer malignancies by utilizing components of immune checkpoint blockades (ICBs), mainly programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), along with elements of adoptive cellular therapies (ACTs) like Chimeric Antigen Receptor (CAR) therapy, T Cell Receptor (TCR) therapy and Tumor-Infiltrating Lymphocyte (TIL) therapy. However, cancer cells tend to undermine the effectiveness of cancer immunotherapeutic strategies by employing one or more immune evasion mechanisms. This review briefly highlights how key mechanisms of cancer immune evasion confer resistance to immunotherapy and how the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR)/Cas9 systems, as gene-editing tools, are poised to enhance cancer immunotherapy for treating challenging cancers. We emphasize that (CRISPR/Cas9) systems can be used to explore and positively alter the genes of the immune system, boosting the effectiveness of cancer immunotherapy by editing immune checkpoints, TILs, and CAR-T cells, and disrupting genes, facilitating tumors’ evasion of the immune system. Furthermore, we highlight the growing interest in emerging base editor technology to engineer natural killer (NK) cells to overcome NK-cell-based immunotherapy challenges, particularly human leukocyte antigens (HLA)-mediated limitations, and to engineer CAR-T cells for improved immunotherapy outcomes. Full article
(This article belongs to the Special Issue Molecular Research for Cancer Immunotherapy)
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19 pages, 1167 KB  
Review
mRNA-Based Neoantigen Vaccines in Pancreatic Ductal Adenocarcinoma (PDAC)—A Promising Avenue in Cancer Immunotherapy
by Jacek Kabut, Małgorzata Stopyra, Natalia Nafalska, Grzegorz J. Stępień, Michał Miciak, Marcin Jezierzański, Tomasz Furgoł, Krzysztof Feret and Iwona Gisterek-Grocholska
Int. J. Mol. Sci. 2025, 26(22), 10988; https://doi.org/10.3390/ijms262210988 - 13 Nov 2025
Cited by 3 | Viewed by 3904
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with 5-year survival rates consistently below 5% despite advances in surgery, chemotherapy, and targeted therapy. Worldwide, PDAC remains highly lethal, with 458,918 new cases and 432,242 deaths in 2018—about a 94% mortality-to-incidence [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with 5-year survival rates consistently below 5% despite advances in surgery, chemotherapy, and targeted therapy. Worldwide, PDAC remains highly lethal, with 458,918 new cases and 432,242 deaths in 2018—about a 94% mortality-to-incidence ratio. The limited therapeutic efficacy is largely attributed to the pronounced heterogeneity of the disease, late clinical presentation, and the strongly immunosuppressive tumor microenvironment. In recent years, mRNA-based vaccines encoding patient-specific neoantigens have emerged as a promising immunotherapeutic modality. By delivering tailored antigenic sequences, these vaccines are capable of eliciting potent cytotoxic T-cell responses against tumor-restricted epitopes, thereby enhancing tumor immunogenicity while minimizing off-target effects. This review summarizes the biological rationale underlying mRNA vaccination in PDAC, recent progress in preclinical and early clinical trials, and key obstacles related to antigen selection, delivery platforms, and the immunosuppressive stroma. The potential integration of neoantigen mRNA vaccines into multimodal therapeutic strategies, including immune checkpoint inhibition and chemotherapy, is also discussed, underscoring their prospective role in overcoming resistance mechanisms and improving clinical outcomes in PDAC. However, most current data come from early-phase trials, with long-term benefits yet unproven. Definitive conclusions on efficacy and survival await results from ongoing randomized studies expected by 2028–2029. Further progress in neoantigen identification, delivery systems, and combination strategies is crucial to fully harness mRNA vaccine potential in PDAC. Full article
(This article belongs to the Special Issue Molecular Research for Cancer Immunotherapy)
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22 pages, 1584 KB  
Review
STINGing Cancer: Development, Clinical Application, and Targeted Delivery of STING Agonists
by Yannick Gabriel Nerdinger, Amanda Katharina Binder, Franziska Bremm, Niklas Feuchter, Niels Schaft and Jan Dörrie
Int. J. Mol. Sci. 2025, 26(18), 9008; https://doi.org/10.3390/ijms26189008 - 16 Sep 2025
Cited by 9 | Viewed by 6338
Abstract
As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of [...] Read more.
As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of cancer. However, response rates even to well-established immunotherapies remain low in several types of cancer. Therefore, various novel immunomodulatory substances are currently under investigation, among them agonists of the intracellular signaling protein STING (STimulator of INterferon Genes). Activation of the STING signaling pathway can alter the cytokine profile within the tumor microenvironment (TME) and reshape the function of various immune cells. STING agonists have yielded promising results in preclinical studies, but this success has not yet been replicated in clinical trials. Consequently, STING agonists are optimized for greater potency and combined with nanotechnologies to enhance biodistribution and achieve sustained accumulation within the TME. This review summarizes a selection of STING agonists evaluated in clinical trials to date and discusses their effects on tumor-infiltration immune cells, especially macrophages. It highlights emerging candidates currently under investigation in preclinical studies, and explores nanotechnological approaches for their combinational use to enhance therapeutic efficacy. Full article
(This article belongs to the Special Issue Molecular Research for Cancer Immunotherapy)
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