Novel Insights into Cancer Immune Responsiveness

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 30 September 2026 | Viewed by 5897

Special Issue Editors


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Guest Editor
Department of Medicine, Duke University, Research Drive, 245 Carl Building, Durham, NC 27707, USA
Interests: immune response; inflammation; macrophages; dendritic cells; stem cells; signaling; calcium; tumor microenvironment; hematopoiesis; radiation
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Guest Editor
Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA, USA
Interests: immune checkpoint inhibitors; cancer immunology; immunotherapy; T cells; CAR-T cells; cancer biology; apoptosis; antibody engineering; microRNAs

Special Issue Information

Dear Colleagues,

Cancer immunotherapies have transformed the landscape of cancer treatment, offering new hope for patients. However, a considerable number still exhibit resistance to these therapies. Over the past two decades, researchers have worked to understand and overcome these challenges, driving advancements in precision medicine and combination strategies. The evolution of cancer immunotherapy began in 1891 when surgeon William Coley successfully treated a cancer patient using a nonspecific toxin composed of heat-killed bacteria. In the 1980s, Steven Rosenberg and his team pioneered adoptive cell therapy (ACT), utilizing tumor-infiltrating lymphocytes (TILs) to treat melanoma patients. Their groundbreaking work provided the first clear evidence that the immune system could be leveraged to boost the effectiveness of cancer treatments. Since then, a wide range of cancer immunotherapies—from broad nonspecific treatments to precisely targeted approaches—have been evaluated. In 2010, significant progress in immunotherapy emerged—with developments like checkpoint inhibitors and CAR-T cell therapy, as well as the U.S. Food and Drug Administration (FDA) approving the first cell-based vaccine for treating metastatic prostate cancer. The following year, the FDA granted approval for the first checkpoint inhibitor drug, an anti-CTLA-4 monoclonal antibody, ipilimumab, for treating metastatic melanoma. In 2013, cancer immunotherapy was named as the “Breakthrough of the Year”. PD-1 inhibitors and bispecific T-cell engagers received their first approval from the FDA in 2014. In 2015, CAR-T cells demonstrated promising results in blood cancers, and by 2017, the first CAR-T therapy was approved for treating young adult and pediatric patients. James P. Allison and Tasuku Honjo, whose groundbreaking research laid the foundation for immune checkpoint inhibitors (ICIs), were honored with the 2018 Nobel Prize in Physiology or Medicine for their discovery of cancer therapy through the inhibition of negative immune regulation. Their work revolutionized cancer treatment by harnessing the body's immune system to combat tumors. As of today, there is at least one checkpoint inhibitor approved for treating more than twenty cancer types. This Special Issue highlights the rapidly evolving landscape of cancer immunotherapy, focusing on key areas such as immune targets and CAR- and TCR-engineered T-cell therapies for various cancer types.

Dr. Luigi Racioppi
Dr. Tanmoy Mondal
Guest Editors

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Keywords

  • cancers
  • tumors
  • immune cells
  • tumor immunology
  • cancer immunology
  • onco-immunology
  • immunotherapies
  • resistance
  • immunotherapy resistance
  • immune checkpoint
  • CAR
  • antibody
  • cancer vaccines

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Published Papers (3 papers)

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Research

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22 pages, 9969 KB  
Article
Immune Cell Modulation of Patient-Matched Organoid Drug Response in Precision Cancer Medicine Platform
by Silje Kjølle, Mario Presti, Jéssica de Pina Roque, Lina Hua Bisgaard, Darío Beceiro Ramos, Kamilla Westarp Zornhagen, Christina Westmose Yde, Ane Yde Schmidt, Perrine Verdys, Martin Højgaard, Ulrik Lassen, Inge Marie Svane, Kristoffer Staal Rohrberg, Marco Donia and Janine T. Erler
Cells 2026, 15(3), 259; https://doi.org/10.3390/cells15030259 - 29 Jan 2026
Cited by 2 | Viewed by 1673
Abstract
Cancer is one of the leading causes of death worldwide, and the majority of cancer-related deaths are caused by cancer that has spread to other organs. Precision cancer medicine (PCM) holds potential to improve outcomes and relies on molecularly matched therapies based on [...] Read more.
Cancer is one of the leading causes of death worldwide, and the majority of cancer-related deaths are caused by cancer that has spread to other organs. Precision cancer medicine (PCM) holds potential to improve outcomes and relies on molecularly matched therapies based on cancer cell specific molecular alterations. The tumor immune microenvironment plays an important role beyond response to therapy; however, this is generally not considered in current PCM platforms. We established patient-matched organoids and immune cell cultures for drug testing in mono- and co-culture treatment setups using three distinct treatment strategies (pretreatment, co-culture treatment, and T-cell bispecific antibody testing). Response to treatment and impact of immune cells were evaluated by tumor cell viability assays and flow cytometry analysis. Phenotypic analysis showed high heterogeneity of tumor-infiltrating lymphocytes (TILs) across the patients and low immune cell portions of organoids, emphasizing the need for a patient-matched co-culture PCM approach. Our in-depth study of three patients revealed an effect of the patients’ immune cells on drug response and T-cell bispecific antibody treatment in vitro. Here, we illustrate a state-of-the-art co-culture PCM pipeline for patient-matched organoids and immune cells replicating patient response to treatment at the time of biopsy. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Immune Responsiveness)
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Review

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32 pages, 1684 KB  
Review
The Role of Raf Kinase Inhibitor Protein (RKIP) in HER2+ Breast Cancer Immune Evasion
by Ania Khachikian, Mai Ho and Benjamin Bonavida
Cells 2026, 15(4), 319; https://doi.org/10.3390/cells15040319 - 8 Feb 2026
Viewed by 981
Abstract
Breast cancer (BC) is a prevalent malignancy worldwide among women. HER2 overexpression in a subset of BC (HER2+ BC) serves as a critical oncogenic driver and contributes to immune evasion. The Raf Kinase Inhibitor Protein (RKIP), a metastasis suppressor and an immune enhancer, [...] Read more.
Breast cancer (BC) is a prevalent malignancy worldwide among women. HER2 overexpression in a subset of BC (HER2+ BC) serves as a critical oncogenic driver and contributes to immune evasion. The Raf Kinase Inhibitor Protein (RKIP), a metastasis suppressor and an immune enhancer, is underexpressed in HER2+ BC. The treatment of HER2+ BC with anti-HER2 mAbs or chemical inhibitors has resulted in significant clinical responses in a subset of patients; however, unresponsiveness in a larger subset was due to acquired and induced resistance. These findings highlight the need for the development of new effective therapies. By analyzing the signaling pathways mediated by both RKIP and HER2 in HER2+ BC, we have found that RKIP and HER2 downstream signaling and inductions showed an inverse relationship. These suggested the presence of a dysregulated RKIP-HER2 axis in HER2+ BC mediating immune evasion. These findings were corroborated by bioinformatic analyses. The immune evasion induced by the overexpression of HER2 was due, in part, to its regulation of the expression of PD-L1, the polarization of TAMs, the infiltration of suppressor cells (Tregs, MDSCs), and the inhibition of anti-tumor CD8+ T cells, resulting in an overall immunosuppressive TME. In contrast, RKIP expression inhibits critical signaling pathways that regulate HER2 expression, including the Raf-MEK-ERK, NF-kB, and PI3K/Akt pathways, thereby aborting HER2-mediated mechanisms of immune evasion. Overall, we analyzed the cross-talk signaling pathways between RKIP and HER2, established a novel dysregulated axis in HER2+ BC, and delineated the various mechanisms involved in the regulation of immune evasion by RKIP and HER2. Hence, we present various therapeutic strategies aimed at targeting the RKIP-HER2 axis in HER2+ BC to circumvent unresponsiveness to therapeutics and immune evasion. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Immune Responsiveness)
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28 pages, 1074 KB  
Review
CAR-NK Engineering to Overcome TME Barriers
by Fahmida Islam, Aleta Pupovac, Richard L. Boyd and Alan O. Trounson
Cells 2026, 15(1), 21; https://doi.org/10.3390/cells15010021 - 22 Dec 2025
Cited by 3 | Viewed by 2751
Abstract
Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their [...] Read more.
Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article
(This article belongs to the Special Issue Novel Insights into Cancer Immune Responsiveness)
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