Cell Therapy in Solid Cancers: Current and Future Landscape

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

Deadline for manuscript submissions: 30 November 2025 | Viewed by 4998

Special Issue Editors


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Guest Editor
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Interests: drug development; phase I clinical trials; solid tumors; gastrointestinal cancers; pancreas cancer; hepatocellular carcinoma

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Guest Editor
Department of Pathology & Laboratory Medicine, University of Pennsylvania, PSM South Tower, 3400 Civic Center Blvd, Rm 9-105, Philadelphia, PA 19104-5156, USA
Interests: CAR; chimeric antigen receptor; immunotherapy; translational sciences; biomarkers; T-cells; hematologic malignancies

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Guest Editor
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Interests: CAR-T; cell therapy; leukemia; myeloma; lymphoma

Special Issue Information

Dear Colleagues,

Our ability to leverage the immune system to treat cancer is now a reality with broad applications across oncology. Using novel designer molecules (e.g., monoclonal antibodies, nano-bodies, BiTEs) to pharmacologically target immune checkpoints and recruit the host’s innate immune effectors directly to the tumor cells has been the main modality so far. This approach achieved long-term remission in a small subset of cancer patients but requires regular administration, and many others will invariably progress.  As such, the idea of introducing manipulated cancer-targeting immune cells into a patient as a “living cure” is highly attractive.

Modified cell therapy, such as CAR-T, is now a standard in several hematologic malignancies and holds great promise in solid tumors. There are different challenges when treating solid tumors, including tumor heterogeneity and a complex tumor microenvironment that may impede treatment delivery and counter the desired anti-cancer immune effects. As the field advances, there will be more scientific and technological questions that need innovative solutions, including enhancing CAR-T therapy, developing “off-the-shelf” anti-cancer cell products, the role of non-T-cells such as NK cells and macrophages, appropriate conditioning regimen, and management of long-term toxicities in survivors. We will continue to innovate because our patients need this.

The excitement of witnessing the dawn of the modified cell therapy era in oncology cannot be understated. In this Special Issue, we have invited subject matter experts to educate us on the current landscape in the clinical development of this modality in treating solid tumors and provide insights into what the future holds. 

Dr. Wenwee Ma
Prof. Dr. Jan Joseph Melenhorst
Dr. Li Yin
Guest Editors

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Keywords

  • cell therapy
  • solid tumors
  • immunotherapy
  • CAR-T
  • NK cell

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Published Papers (2 papers)

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Review

16 pages, 691 KiB  
Review
Engineering Innate Immunity: Recent Advances and Future Directions for CAR-NK and CAR–Macrophage Therapies in Solid Tumors
by Behzad Amoozgar, Ayrton Bangolo, Charlene Mansour, Daniel Elias, Abdifitah Mohamed, Danielle C. Thor, Syed Usman Ehsanullah, Hadrian Hoang-Vu Tran, Izage Kianifar Aguilar and Simcha Weissman
Cancers 2025, 17(14), 2397; https://doi.org/10.3390/cancers17142397 - 19 Jul 2025
Viewed by 564
Abstract
Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered [...] Read more.
Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK+ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article
(This article belongs to the Special Issue Cell Therapy in Solid Cancers: Current and Future Landscape)
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26 pages, 1561 KiB  
Review
Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy
by Neda Dadgar, Arun K. Arunachalam, Hanna Hong, Yee Peng Phoon, Jorge E. Arpi-Palacios, Melis Uysal, Chase J. Wehrle, Federico Aucejo, Wen Wee Ma and Jan Joseph Melenhorst
Cancers 2024, 16(18), 3232; https://doi.org/10.3390/cancers16183232 - 23 Sep 2024
Cited by 4 | Viewed by 3747
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based [...] Read more.
Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment. Full article
(This article belongs to the Special Issue Cell Therapy in Solid Cancers: Current and Future Landscape)
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