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New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (15 January 2026) | Viewed by 14097

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Special Issue Editor

Dr. Xiaotong Song

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Guest Editor

Translational Medical Sciences, Texas A&M University, Bryan, TX, USA
Interests: cancer immunotherapy; CAR T cell therapy; antitumor immunity

Special Issue Information

Dear Colleagues,

The landscape of cancer immunotherapy is rapidly expanding, driven by advancements in the harnessing of various immune cell types to combat cancer. This Special Issue highlights recent breakthroughs in immunotherapy, encompassing T cells, natural killer (NK) cells, dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), and other immune components shaping anti-tumor responses. We welcome studies on engineered immune cell therapies, bispecific immune engagers, immune checkpoint modulation, and novel combination strategies for enhancing therapeutic efficacy and overcoming resistance. Additionally, contributions on tumor microenvironment interactions, mechanisms of immune evasion, and translational research connecting preclinical discoveries to clinical practice are highly encouraged. Through this Special Issue, we seek to provide comprehensive insights into the evolving field of cancer immunotherapy and its impact on patient outcomes.

Dr. Xiaotong Song
Guest Editor

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Keywords

T cell therapy
cancer immunotherapy
CAR T cells
immune checkpoint modulation
tumor microenvironment

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Published Papers (6 papers)

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Research

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15 pages, 2473 KB

Open AccessArticle

CV1 Chimpanzee Adenovirus Efficiently Transduces Mesenchymal Stem and Leukemia Cells: Implications for Cellular Targeting and Vector Tropism

by Lorella Tripodi, Maria Vitale, Barbara Izzo, Filippo Scialò, Barbara Lombardo and Lucio Pastore

Cancers 2026, 18(2), 220; https://doi.org/10.3390/cancers18020220 - 9 Jan 2026

Viewed by 573

Abstract

Objectives: Adenoviruses (Ads) are among the most used vectors for gene therapy; human Ad serotype 5-derived (HuAd5) vectors are the most frequently used for gene transfer applications. However, Ad5 infection is endemic in humans, and 20% of the Western population has neutralizing antibodies (nAbs). Pre-existing immunity against HuAd5 represents a major issue for many gene therapy applications. In our study, we evaluated several Ad serotypes derived from chimpanzees (ChAds) in vitro and in vivo to assess their transduction efficiency in various cell types and tissues. We aimed at identifying Ad serotypes able either to transduce “challenging” cell types or to represent a possible alternative to Ad5-derived vectors with comparable infectivity and tropism. Methods: We evaluated the efficacy of transduction of twelve ChAds vectors expressing enhanced green fluorescent protein (EGFP) in human embryonic kidney cells, as well as human leukemic and human mesenchymal stem cells, using flow cytometry to determine the percentage of EGFP-expressing cells and their mean fluorescent intensity (MFI). We observed the highest transduction efficiency in the serotype CV1 ChAd; therefore, we proceeded to evaluate toxicity and biodistribution in vivo. Results: After in vitro evaluation of twelve ChAds serotypes, we observed that the CV1 serotype was the most efficient in transducing both leukemia cell lines (HL-60 and NB-4) and human mesenchymal stem cells. Furthermore, in vivo analysis of the CV1 serotype induced an inflammatory reaction similar to what was observed after HuAd5 administration. Conclusions: ChAds vectors represent an effective alternative for the transduction of cells resistant to HuAd5 infection, such as mesenchymal stem cells and leukemic cells. In addition, we observed that the CV1 ChAd serotype presented a transduction profile similar to HuAd5 in vitro and induced a similar inflammatory response in vivo; therefore, CV1 ChAd-derived vectors represent an interesting alternative for gene therapy applications. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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22 pages, 1820 KB

Open AccessEditor’s ChoiceArticle

Supercharged Natural Killer (sNK) Cells Inhibit Melanoma Tumor Progression and Restore Endogenous NK Cell Function in Humanized BLT Mice

by Kawaljit Kaur, Paytsar Topchyan and Anahid Jewett

Cancers 2025, 17(15), 2430; https://doi.org/10.3390/cancers17152430 - 23 Jul 2025

Cited by 6 | Viewed by 2041

Abstract

Background: We have previously shown the remarkable impact of a single infusion of supercharged NK cells (sNK) in preventing and eliminating oral, pancreatic, and uterine cancers implanted in humanized BLT (hu-BLT) mice. Objective: In this report, we extended the studies to melanoma tumors to observe whether there were differences in response to sNK cells. Methods: We investigated the safety and tissue biodistribution profile of sNK cells in hu-BLT mice. This included the effect of sNK cell therapy on the peripheral blood-derived PBMCs, bone marrow, and spleen of hu-BLT mice. Results: Our investigation showed promising outcomes, as sNK cell infusions effectively inhibited melanoma tumor growth in hu-BLT mice. These potent cells not only traversed through the peripheral blood, spleen, and bone marrow but also infiltrated the tumor site, triggering in vivo differentiation of melanoma tumors. Moreover, the infusion of sNK cells increased the percentages of NK cells in the peripheral blood of hu-BLT mice, restoring cytotoxicity and IFN-γ secretion within the peripheral blood, spleen, and bone marrow of melanoma-bearing mice. Conclusions: This therapeutic approach not only reversed tumor progression but also revitalized the functionality of endogenous NK cells, potentially reversing the immunosuppressive effects induced by tumor cells in cancer patients. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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Review

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18 pages, 1445 KB

Open AccessReview

ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors

by Alex Wade Song and Xiaotong Song

Cancers 2026, 18(1), 34; https://doi.org/10.3390/cancers18010034 - 22 Dec 2025

Cited by 2 | Viewed by 1121

Abstract

CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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31 pages, 1513 KB

Open AccessReview

Natural Killer (NK) Cell-Based Therapies Have the Potential to Treat Ovarian Cancer Effectively by Targeting Diverse Tumor Populations and Reducing the Risk of Recurrence

by Kawaljit Kaur

Cancers 2025, 17(23), 3862; https://doi.org/10.3390/cancers17233862 - 1 Dec 2025

Cited by 1 | Viewed by 3353

Abstract

Ovarian cancer is the sixth leading cause of cancer-related deaths among women in the United States. This complex disease arises from tissues such as the ovarian surface epithelium, fallopian tube epithelium, endometrium, or ectopic Müllerian components and is characterized by diverse histological and molecular traits. Standard treatments like surgery, chemotherapy, and radiation have limited effectiveness and high toxicity. Targeted therapies, including poly (ADP-ribose) polymerase PARP inhibitors, anti-angiogenics, and immune checkpoint inhibitors (ICIs), face obstacles such as adaptive resistance and microenvironmental barriers that affect drug delivery and immune responses. Factors in the tumor microenvironment, such as dense stroma, hypoxia, immune suppression, cancer stem cells (CSCs), and angiogenesis, can reduce drug efficacy, worsen prognosis, and increase the risk of recurrence. Research highlights impaired immune function in ovarian cancer patients as a contributor to recurrence, emphasizing the importance of immunotherapies to target tumors and restore immune function. Preclinical studies and early clinical trials found that natural killer (NK) cell-based therapies have great potential to tackle ovarian tumors. This review explores the challenges and opportunities in treating ovarian cancer, focusing on how NK cells could help overcome these obstacles. Recent findings reveal that engineered NK cells, unlike their primary NK cells, can destroy both stem-like and differentiated ovarian tumors, pointing to their ability to target diverse tumor types. Animal studies on NK cell therapies for solid cancers have shown smaller tumor sizes, tumor differentiation in vivo, recruitment of NK and T cells in the tumor environment and peripheral tissues, restored immune function, and fewer tumor-related systemic effects—suggesting a lower chance of recurrence. NK cells clinical trials in ovarian cancer patients have also shown encouraging results, and future directions include combining NK cell therapies with standard treatments to potentially boost effectiveness. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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24 pages, 1565 KB

Open AccessReview

Influence of Genetic, Dietary, and Environmental Factors on Natural Killer (NK) Cell Biology and Function: Interplay Between NK Cell Activity and Cancer Onset or Progression

by Kawaljit Kaur

Cancers 2025, 17(18), 2946; https://doi.org/10.3390/cancers17182946 - 9 Sep 2025

Viewed by 3861

Abstract

The connection between NK cells and cancer offers valuable insights into disease management. Suppressing NK cells can encourage cancer growth, while cancer itself can weaken NK cell function. This review examines how genetic and environmental factors such as diet affect NK cell numbers and function during the early stages of cancer. It also explores the reduced NK cell activity in cancer-bearing mouse models and human patients. The mechanisms behind cytotoxic actions and cytokine release are analyzed across four NK cell maturation stages. This understanding highlights the potential of using healthy donor NK cells for immunotherapy, alongside the role of memory NK cells in treatments. While NK cell-based therapies show promise in studies, challenges remain in sustaining their effectiveness and durability. This review also discusses strategies to improve production and boost the efficiency of donor NK cell therapies. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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14 pages, 581 KB

Open AccessReview

CAR-Based Cell Therapy in Head and Neck Cancer: A Comprehensive Review on Clinical Applicability

by Francesco Perri, Margaret Ottaviano, Miriam Tomaciello and Francesca De Felice

Cancers 2025, 17(13), 2215; https://doi.org/10.3390/cancers17132215 - 1 Jul 2025

Cited by 2 | Viewed by 2450

Abstract

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy is a novel form of adoptive cellular immunotherapy that involves modifying autologous T cells to recognize and target tumor-associated antigens (TAAs) on malignant cells, independent of major histocompatibility complex (MHC) restriction. Although CAR-T therapy has shown remarkable success in treating hematologic malignancies, its efficacy in solid tumors remains limited, largely due to the lack of tumor-specific antigens and the complexity of the tumor microenvironment. This review aims to explore the rationale for continuing the development of adoptive cellular therapies in head and neck cancer (HNC), offering insights into the diagnostic and therapeutic challenges associated with this heterogeneous group of malignancies. Methods: We conducted a comprehensive literature review using the PubMed database to identify relevant studies on the application of CAR-T cell therapy in the management of HNC. Results: HNC presented numerous barriers to CAR-T cell infiltration, primarily due to the unique characteristics of its tumor microenvironment (TME). The TME in HNC is notably immunosuppressive, with a lymphocytic infiltrate predominantly composed of regulatory T cells (Tregs) and natural killer (NK) cells. These immune cells typically exhibit low expression of the CD16 receptor, which plays a crucial role in mediating antibody-dependent cellular cytotoxicity (ADCC), thereby limiting the effectiveness of CAR-T cell therapy. Conclusions: This comprehensive review suggests a potential clinical applicability of CAR-T therapy in HNC management. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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