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Mechanistic Insights into Cancer Immunotherapy and Immune-Related Adverse Events
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Mechanistic Insights into Cancer Immunotherapy and Immune-Related Adverse Events

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 (20 October 2025) | Viewed by 5440

Special Issue Editors

Dr. Noha Abdel-Wahab

E-Mail Website
Guest Editor
Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine and Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: cancer immunotherapy; immune-related adverse events; biomarker
Dr. Bilal A. Siddiqui

E-Mail Website
Guest Editor
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: immune system; cancer immunotherapy; cancer progression
Dr. Kristen E. Pauken

E-Mail Website
Guest Editor
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: tumor immune microenvironment; PD-1 immunotherapy; CD8+ T cells; T cell exhaustion; immune-related adverse events; autoimmunity; melanoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the rapid evolution of cancer immunotherapy, its role in clinical treatment has become increasingly prominent. Current research in cancer immunotherapy is dedicated to recognizing and treating immune-related adverse events (irAEs) without compromising the efficacy of cancer treatment. However, the pathophysiological mechanisms underlying irAEs are not fully understood, which limits the development of targeted therapies. irAEs associated with immunotherapy remain a complex and challenging field. For this Special Issue, we are particularly interested in papers that can translate basic scientific research into clinical applications. This includes, but is not limited to, the following:

  • The molecular and cellular mechanisms of irAEs in cancer immunotherapy.
  • The discovery and validation of predictive biomarkers and their application in early diagnosis and personalized treatment.
  • The development and evaluation of evidence-based treatment methods for specific types of irAEs.
  • Multidisciplinary research approaches to address technical and methodological limitations in irAEs research.

This will be lead by Dr. Noha Abdel-Wahab, Dr. Bilal A. Siddiqui, and Dr. Kristen E. Pauken and assisted by our Topical Advisory Panel Member Dr. Avik Dutta (National Institute of Child Health and Human Development). We invite researchers, clinicians, and scientists to submit original molecular research, reviews, and case reports on the mechanisms, diagnosis, treatment, and management strategies of cancer immunotherapy and its related irAEs. We anticipate that your contributions will provide new insights into the safety and efficacy of cancer immunotherapy.

Dr. Noha Abdel-Wahab
Dr. Bilal A. Siddiqui
Dr. Kristen E. Pauken
Guest Editors

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
  • immune-related adverse events
  • biomarker
  • immune checkpoint inhibitor
  • cancer progression

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Published Papers (3 papers)

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Research

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18 pages, 2185 KB  
Article
Analyses of Exosomal HER2 in Breast Cancer and the Effect of Respective Exosome-Immune Complexes on Trastuzumab-Based Immunotherapy
by Jordan Gorospe, Marjorie Shapiro and Venkateswara R. Simhadri
Int. J. Mol. Sci. 2025, 26(21), 10331; https://doi.org/10.3390/ijms262110331 - 23 Oct 2025
Viewed by 715
Abstract
Monoclonal antibodies like trastuzumab have shown clinical success in cancer treatment, but patient responses vary, and resistance can develop, possibly due to tumor microenvironment factors. In this study, we explored the role of HER2-positive exosomes in counteracting one of the mechanisms of action [...] Read more.
Monoclonal antibodies like trastuzumab have shown clinical success in cancer treatment, but patient responses vary, and resistance can develop, possibly due to tumor microenvironment factors. In this study, we explored the role of HER2-positive exosomes in counteracting one of the mechanisms of action of trastuzumab: antibody-dependent cell-mediated cytotoxicity (ADCC). We conducted a comprehensive analysis of HER2 expression on exosomes purified from the plasma of breast cancer patients and different breast cancer cell lines using various purification methods. Purified exosomes were analyzed using the single-particle interferometric reflectance imaging sensor (SP-IRIS)-based ExoView platform. To gain better insight into the formation of exosomal-immune complexes with trastuzumab, we used the ExoView platform to analyze the CD9/HER2/Human IgG phenotype of exosomes at the single vesicle level. Additionally, in a standard functional ADCC assay, formation of exosome-immune complexes with trastuzumab reduced the killing of breast cancer target cells. Together, our findings show that exosomes can function as decoys for immunotherapy, reducing its efficacy, and that SP-IRIS-based analysis can be used to identify levels of HER2-expressing exosomes in patients, which could aid in patient management. Full article
(This article belongs to the Special Issue Mechanistic Insights into Cancer Immunotherapy and Immune-Related Adverse Events)
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15 pages, 3568 KB  
Article
TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab
by Bunpei Isoda, Shuya Kandori, Tomokazu Sazuka, Takahiro Kojima, Satoshi Nitta, Masanobu Shiga, Yoshiyuki Nagumo, Ayumi Fujimoto, Takayuki Arai, Hiroaki Sato, Bryan J. Mathis, Chia-Ling Wu, Yi-Hua Jan, Tomohiko Ichikawa and Hiroyuki Nishiyama
Int. J. Mol. Sci. 2024, 25(13), 7444; https://doi.org/10.3390/ijms25137444 - 6 Jul 2024
Cited by 1 | Viewed by 3068
Abstract
Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is [...] Read more.
Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection. Full article
(This article belongs to the Special Issue Mechanistic Insights into Cancer Immunotherapy and Immune-Related Adverse Events)
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Review

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37 pages, 1441 KB  
Review
Soil and Seed: Tumor Microenvironment Nurtures Immunotherapy Resistance and Renewal
by Yiya Li, Qiushi Feng, Yangyang Xia, Lingzi Liao and Shang Xie
Int. J. Mol. Sci. 2025, 26(21), 10547; https://doi.org/10.3390/ijms262110547 - 30 Oct 2025
Viewed by 898
Abstract
Cancer immunotherapy has become a powerful clinical strategy for cancer management, while its efficacy is frequently limited by primary and acquired resistance. The tumor microenvironment (TME) plays a pivotal role in mediating such resistance through multifaceted mechanisms involving cellular, metabolic, mechanical, and microbial [...] Read more.
Cancer immunotherapy has become a powerful clinical strategy for cancer management, while its efficacy is frequently limited by primary and acquired resistance. The tumor microenvironment (TME) plays a pivotal role in mediating such resistance through multifaceted mechanisms involving cellular, metabolic, mechanical, and microbial components. This review systematically examines how the TME contributes to immunotherapy failure. We compare resistance mechanisms common to both immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapies, two cornerstone modalities in clinical practice. Furthermore, we discuss emerging strategies designed to overcome these barriers, including immune microenvironment, stromal normalization, metabolic modulation, and microbiota engineering. By integrating recent preclinical and clinical insights, this review aims to provide a comprehensive framework for understanding and targeting microenvironmental resistance, ultimately facilitating the translation of novel combination therapies into improved patient outcomes. Full article
(This article belongs to the Special Issue Mechanistic Insights into Cancer Immunotherapy and Immune-Related Adverse Events)
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