Unconventional Immunotherapies in Cancer: Opportunities and Challenges
Abstract
1. Introduction
2. Unconventional Cell-Based Therapies
2.1. Invariant Natural Killer T Cells
2.2. Mucosal-Associated Invariant T Cells
2.3. Gamma Delta T Cells
2.4. Double-Negative T Cells and Engineered Regulatory T Cells
3. Unconventional Biologics
4. Distinct Immune Features of Unconventional Platforms
4.1. MHC-Independence
4.2. Stress Ligand and Metabolite Sensing
4.3. Reduced Risk of GvHD and Alloreactivity
4.4. Immune Bridging Functions
4.5. Tissue Homing and Residency
4.6. Rapid Effector Function
4.7. Suitability for Engineering
5. Translational Challenges
5.1. Phenotypic and Functional Heterogeneity
5.2. Poorly Defined Exhaustion in Unconventional Immune Cells
5.3. Suppression by the Tumor Microenvironment (TME)
5.4. Limited Persistence and Expansion In Vivo
6. Off-the-Shelf Immunotherapies: Cross-Platform Potential
7. Integrating Modalities and Personalization
8. Novel Strategies to Overcome Translational Barriers
8.1. Synthetic Control Systems
8.2. Metabolic Reprogramming
8.3. Epigenetic Modulation
8.4. Immune Cloaking via Gene Editing
8.5. Tumor-Responsive Payload Systems
8.6. Spatial and AI-Guided Stratification
9. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Dummer, R.; Smylie, M.; Rutkowski, P.; et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N. Engl. J. Med. 2015, 373, 23–34. [Google Scholar] [CrossRef]
- Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef] [PubMed]
- Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef]
- Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef]
- Han, Y.; Liu, D.; Li, L. PD-1/PD-L1 pathway: Current researches in cancer. Am. J. Cancer Res. 2020, 10, 727–742. [Google Scholar]
- Dana, H.; Chalbatani, G.M.; Jalali, S.A.; Mirzaei, H.R.; Grupp, S.A.; Suarez, E.R.; Rapôso, C.; Webster, T.J. CAR-T cells: Early successes in blood cancer and challenges in solid tumors. Acta Pharm. Sin. B 2021, 11, 1129–1147. [Google Scholar] [CrossRef]
- Le, J.; Sun, Y.; Deng, G.; Dian, Y.; Xie, Y.; Zeng, F. Immune checkpoint inhibitors in cancer patients with autoimmune disease: Safety and efficacy. Hum. Vaccines Immunother. 2025, 21, 2458948. [Google Scholar] [CrossRef]
- Liu, Y.T.; Sun, Z.J. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics 2021, 11, 5365–5386. [Google Scholar] [CrossRef]
- Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science 2018, 359, 1350–1355. [Google Scholar] [CrossRef]
- Zhang, Z.; Meng, X.; Han, L. Application and Perspectives of Immunotherapy in Head and Neck Squamous Cell Carcinoma. Immunology 2025. early view. [Google Scholar] [CrossRef]
- June, C.H.; O’Connor, R.S.; Kawalekar, O.U.; Ghassemi, S.; Milone, M.C. CAR T cell immunotherapy for human cancer. Science 2018, 359, 1361–1365. [Google Scholar] [CrossRef]
- Kurioka, A.; Klenerman, P. Aging unconventionally: γδ T cells, iNKT cells, and MAIT cells in aging. Semin. Immunol. 2023, 69, 101816. [Google Scholar] [CrossRef] [PubMed]
- Godfrey, D.I.; Uldrich, A.P.; McCluskey, J.; Rossjohn, J.; Moody, D.B. The burgeoning family of unconventional T cells. Nat. Immunol. 2015, 16, 1114–1123. [Google Scholar] [CrossRef] [PubMed]
- Qin, Y.; Oh, S.; Lim, S.; Shin, J.H.; Yoon, M.S.; Park, S.-H. Invariant NKT cells facilitate cytotoxic T-cell activation via direct recognition of CD1d on T cells. Exp. Mol. Med. 2019, 51, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.-R.; Zhou, K.; Wilson, M.; Kramer, A.; Zhu, Y.; Dawson, N.; Yang, L. Mucosal-associated invariant T cells for cancer immunotherapy. Mol. Ther. 2023, 31, 631–646. [Google Scholar] [CrossRef]
- Kabelitz, D.; Serrano, R.; Kouakanou, L.; Peters, C.; Kalyan, S. Cancer immunotherapy with γδ T cells: Many paths ahead of us. Cell. Mol. Immunol. 2020, 17, 925–939. [Google Scholar] [CrossRef]
- Requejo Cier, C.J.; Valentini, N.; Lamarche, C. Unlocking the potential of Tregs: Innovations in CAR technology. Front. Mol. Biosci. 2023, 10, 1267762. [Google Scholar] [CrossRef]
- Schlegel, L.S.; Werbrouck, C.; Boettcher, M.; Schlegel, P. Universal CAR 2.0 to overcome current limitations in CAR therapy. Front. Immunol. 2024, 15, 1383894. [Google Scholar] [CrossRef]
- Heczey, A.; Xu, X.; Courtney, A.N.; Tian, G.; Barragan, G.A.; Guo, L.; Amador, C.M.; Ghatwai, N.; Rathi, P.; Wood, M.S.; et al. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: Updated phase 1 trial interim results. Nat. Med. 2023, 29, 1379–1388. [Google Scholar] [CrossRef]
- Rotolo, A.; Caputo, V.S.; Holubova, M.; Baxan, N.; Dubois, O.; Chaudhry, M.S.; Xiao, X.; Goudevenou, K.; Pitcher, D.S.; Petevi, K.; et al. Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting. Cancer Cell 2018, 34, 596–610.e511. [Google Scholar] [CrossRef]
- Li, Y.-R.; Zhou, Y.; Yu, J.; Kim, Y.J.; Li, M.; Lee, D.; Zhou, K.; Chen, Y.; Zhu, Y.; Wang, Y.-C.; et al. Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method. Nat. Biotechnol. 2025, 43, 329–344. [Google Scholar] [CrossRef] [PubMed]
- Landoni, E.; Woodcock, M.G.; Barragan, G.; Casirati, G.; Cinella, V.; Stucchi, S.; Flick, L.M.; Withers, T.A.; Hudson, H.; Casorati, G.; et al. IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity. Nat. Commun. 2024, 15, 89. [Google Scholar] [CrossRef] [PubMed]
- Qu, J.; Wu, B.; Chen, L.; Wen, Z.; Fang, L.; Zheng, J.; Shen, Q.; Heng, J.; Zhou, J.; Zhou, J. CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy. J. Exp. Clin. Cancer Res. 2024, 43, 134. [Google Scholar] [CrossRef]
- Ruf, B.; Bruhns, M.; Babaei, S.; Kedei, N.; Ma, L.; Revsine, M.; Benmebarek, M.-R.; Ma, C.; Heinrich, B.; Subramanyam, V.; et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell 2023, 186, 3686–3705.e3632. [Google Scholar] [CrossRef]
- Zheng, X.; Wang, X.; Cheng, X.; Liu, Z.; Yin, Y.; Li, X.; Huang, Z.; Wang, Z.; Guo, W.; Ginhoux, F.; et al. Single-cell analyses implicate ascites in remodeling the ecosystems of primary and metastatic tumors in ovarian cancer. Nat. Cancer 2023, 4, 1138–1156. [Google Scholar] [CrossRef]
- Dogan, M.; Karhan, E.; Kozhaya, L.; Placek, L.; Chen, X.; Yigit, M.; Unutmaz, D. Engineering Human MAIT Cells with Chimeric Antigen Receptors for Cancer Immunotherapy. J. Immunol. 2022, 209, 1523–1531. [Google Scholar] [CrossRef]
- Chien, Y.-h.; Meyer, C.; Bonneville, M. γδ T Cells: First Line of Defense and Beyond. Annu. Rev. Immunol. 2014, 32, 121–155. [Google Scholar] [CrossRef]
- Andrlova, H.; Miltiadous, O.; Dai, A.; Gardner, R.; El Daker, S.; Slingerland, J.B.; Giardina, P.A.; Clurman, A.; Gomes, A.L.C.; Nguyen, C.L.; et al. MAIT and Vδ2 Unconventional T Cells Predict Favorable Outcome after Allogeneic HCT and Are Supported by a Diverse Intestinal Microbiome. Blood 2021, 138, 331. [Google Scholar] [CrossRef]
- Jiang, L.; You, F.; Wu, H.; Qi, C.; Xiang, S.; Zhang, P.; Meng, H.; Wang, M.; Huang, J.; Li, Y.; et al. B7-H3–Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity against Solid Tumors. Cancer Res. 2024, 84, 4066–4080. [Google Scholar] [CrossRef]
- Lee, D.; Dunn, Z.S.; Guo, W.; Rosenthal, C.J.; Penn, N.E.; Yu, Y.; Zhou, K.; Li, Z.; Ma, F.; Li, M.; et al. Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering. Nat. Commun. 2023, 14, 6942. [Google Scholar] [CrossRef]
- Tin, E.; Lee, J.B.; Khatri, I.; Na, Y.; Minden, M.D.; Zhang, L. Double-negative T cells utilize a TNFα–JAK1–ICAM-1 cytotoxic axis against acute myeloid leukemia. Blood Adv. 2024, 8, 3013–3026. [Google Scholar] [CrossRef]
- Zhang, Q.; Lu, W.; Liang, C.-L.; Chen, Y.; Liu, H.; Qiu, F.; Dai, Z. Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance. Front. Immunol. 2018, 9, 2359. [Google Scholar] [CrossRef]
- Togashi, Y.; Shitara, K.; Nishikawa, H. Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nat. Rev. Clin. Oncol. 2019, 16, 356–371. [Google Scholar] [CrossRef] [PubMed]
- Tapia-Galisteo, A.; Álvarez-Vallina, L.; Sanz, L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J. Hematol. Oncol. 2023, 16, 83. [Google Scholar] [CrossRef] [PubMed]
- Zarezadeh Mehrabadi, A.; Tat, M.; Ghorbani Alvanegh, A.; Roozbahani, F.; Esmaeili Gouvarchin Ghaleh, H. Revolutionizing cancer treatment: The power of bi- and tri-specific T-cell engagers in oncolytic virotherapy. Front. Immunol. 2024, 15, 1343378. [Google Scholar] [CrossRef]
- Mocquot, P.; Mossazadeh, Y.; Lapierre, L.; Pineau, F.; Despas, F. The pharmacology of blinatumomab: State of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials. J. Clin. Pharm. Ther. 2022, 47, 1337–1351. [Google Scholar] [CrossRef]
- Tapia-Galisteo, A.; Compte, M.; Álvarez-Vallina, L.; Sanz, L. When three is not a crowd: Trispecific antibodies for enhanced cancer immunotherapy. Theranostics 2023, 13, 1028–1041. [Google Scholar] [CrossRef]
- Rolin, C.; Zimmer, J.; Seguin-Devaux, C. Bridging the gap with multispecific immune cell engagers in cancer and infectious diseases. Cell. Mol. Immunol. 2024, 21, 643–661. [Google Scholar] [CrossRef]
- Kourilsky, P.; Truffa-Bachi, P. Cytokine fields and the polarization of the immune response. Trends Immunol. 2001, 22, 502–509. [Google Scholar] [CrossRef]
- Zhang, J.; Zhao, X. Administration of fusion cytokines induces tumor regression and systemic antitumor immunity. MedComm 2021, 2, 256–268. [Google Scholar] [CrossRef]
- Dunn, G.P.; Koebel, C.M.; Schreiber, R.D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 2006, 6, 836–848. [Google Scholar] [CrossRef]
- Weiss, J.M.; Subleski, J.J.; Wigginton, J.M.; Wiltrout, R.H. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert. Opin. Biol. Ther. 2007, 7, 1705–1721. [Google Scholar] [CrossRef] [PubMed]
- Atkins, M.B.; Robertson, M.J.; Gordon, M.; Lotze, M.T.; DeCoste, M.; DuBois, J.S.; Ritz, J.; Sandler, A.B.; Edington, H.D.; Garzone, P.D.; et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin. Cancer Res. 1997, 3, 409–417. [Google Scholar] [PubMed]
- Portielje, J.E.; Kruit, W.H.; Schuler, M.; Beck, J.; Lamers, C.H.; Stoter, G.; Huber, C.; de Boer-Dennert, M.; Rakhit, A.; Bolhuis, R.L.; et al. Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer. Clin. Cancer Res. 1999, 5, 3983–3989. [Google Scholar] [PubMed]
- Möller, A.M.; Vettermann, S.; Baumann, F.; Pütter, M.; Müller, D. Trifunctional antibody-cytokine fusion protein formats for tumor-targeted combination of IL-15 with IL-7 or IL-21. Front. Immunol. 2025, 16, 1498697. [Google Scholar] [CrossRef]
- Bai, Y.; Hui, P.; Du, X.; Su, X. Updates to the antitumor mechanism of oncolytic virus. Thorac. Cancer 2019, 10, 1031–1035. [Google Scholar] [CrossRef]
- Kooti, W.; Esmaeili Gouvarchin Ghaleh, H.; Farzanehpour, M.; Dorostkar, R.; Jalali Kondori, B.; Bolandian, M. Oncolytic Viruses and Cancer, Do You Know the Main Mechanism? Front. Oncol. 2021, 11, 761015. [Google Scholar] [CrossRef]
- Lin, D.; Shen, Y.; Liang, T. Oncolytic virotherapy: Basic principles, recent advances and future directions. Signal Transduct. Target. Ther. 2023, 8, 156. [Google Scholar] [CrossRef]
- Zhang, H.; Ren, Y.; Wang, F.; Tu, X.; Tong, Z.; Liu, L.; Zheng, Y.; Zhao, P.; Cheng, J.; Li, J.; et al. The long-term effectiveness and mechanism of oncolytic virotherapy combined with anti-PD-L1 antibody in colorectal cancer patient. Cancer Gene Ther. 2024, 31, 1412–1426. [Google Scholar] [CrossRef]
- DePeaux, K.; Rivadeneira, D.B.; Lontos, K.; Dean, V.G.; Gunn, W.G.; Watson, M.J.; Yao, T.; Wilfahrt, D.; Hinck, C.; Wieteska, L.; et al. An oncolytic virus–delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment. J. Exp. Med. 2023, 220, e20230053. [Google Scholar] [CrossRef]
- Andtbacka, R.H.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients with Advanced Melanoma. J. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef]
- Chandran, S.S.; Klebanoff, C.A. T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance. Immunol. Rev. 2019, 290, 127–147. [Google Scholar] [CrossRef] [PubMed]
- Swieboda, D.; Rice, T.F.; Guo, Y.; Nadel, S.; Thwaites, R.S.; Openshaw, P.J.M.; Holder, B.; Culley, F.J. Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth. Clin. Exp. Immunol. 2024, 215, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Dhatchinamoorthy, K.; Colbert, J.D.; Rock, K.L. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front. Immunol. 2021, 12, 636568. [Google Scholar] [CrossRef] [PubMed]
- Pardoll, D. Cancer and the Immune System: Basic Concepts and Targets for Intervention. Semin. Oncol. 2015, 42, 523–538. [Google Scholar] [CrossRef]
- Herrmann, T.; Karunakaran, M.M. Phosphoantigen recognition by Vγ9Vδ2 T cells. Eur. J. Immunol. 2024, 54, 2451068. [Google Scholar] [CrossRef]
- Edmans, M.D.; Connelley, T.K.; Morgan, S.; Pediongco, T.J.; Jayaraman, S.; Juno, J.A.; Meehan, B.S.; Dewar, P.M.; Maze, E.A.; Roos, E.O.; et al. MAIT cell-MR1 reactivity is highly conserved across multiple divergent species. J. Biol. Chem. 2024, 300, 107338. [Google Scholar] [CrossRef]
- Anfossi, N.; André, P.; Guia, S.; Falk, C.S.; Roetynck, S.; Stewart, C.A.; Breso, V.; Frassati, C.; Reviron, D.; Middleton, D.; et al. Human NK Cell Education by Inhibitory Receptors for MHC Class I. Immunity 2006, 25, 331–342. [Google Scholar] [CrossRef]
- Xie, N.; Shen, G.; Gao, W.; Huang, Z.; Huang, C.; Fu, L. Neoantigens: Promising targets for cancer therapy. Signal Transduct. Target. Ther. 2023, 8, 9. [Google Scholar] [CrossRef]
- Gleimer, M.; Parham, P. Stress Management: MHC Class I and Class I-like Molecules as Reporters of Cellular Stress. Immunity 2003, 19, 469–477. [Google Scholar] [CrossRef]
- Liu, H.; Wang, S.; Xin, J.; Wang, J.; Yao, C.; Zhang, Z. Role of NKG2D and its ligands in cancer immunotherapy. Am. J. Cancer Res. 2019, 9, 2064–2078. [Google Scholar]
- Hoeres, T.; Smetak, M.; Pretscher, D.; Wilhelm, M. Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer. Front. Immunol. 2018, 9, 800. [Google Scholar] [CrossRef] [PubMed]
- Prasad, S.; Singh, S.; Menge, S.; Mohapatra, I.; Kim, S.; Helland, L.; Singh, G.; Singh, A. Gut redox and microbiome: Charting the roadmap to T-cell regulation. Front. Immunol. 2024, 15, 1387903. [Google Scholar] [CrossRef] [PubMed]
- Hu, Y.; Hu, Q.; Li, Y.; Lu, L.; Xiang, Z.; Yin, Z.; Kabelitz, D.; Wu, Y. γδ T cells: Origin and fate, subsets, diseases and immunotherapy. Signal Transduct. Target. Ther. 2023, 8, 434. [Google Scholar] [CrossRef] [PubMed]
- Lonez, C.; Breman, E. Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met? Cells 2024, 13, 146. [Google Scholar] [CrossRef]
- Li, Y.-R.; Zhu, Y.; Chen, Y.; Yang, L. The clinical landscape of CAR-engineered unconventional T cells. Trends Cancer 2025, 11, 520–539. [Google Scholar] [CrossRef]
- Sullivan, L.C.; Shaw, E.M.; Stankovic, S.; Snell, G.I.; Brooks, A.G.; Westall, G.P. The complex existence of γδ T cells following transplantation: The good, the bad and the simply confusing. Clin. Transl. Immunol. 2019, 8, e1078. [Google Scholar] [CrossRef]
- Berrien-Elliott, M.M.; Jacobs, M.T.; Fehniger, T.A. Allogeneic natural killer cell therapy. Blood 2023, 141, 856–868. [Google Scholar] [CrossRef]
- Krovi, S.H.; Loh, L.; Spengler, A.; Brunetti, T.; Gapin, L. Current insights in mouse iNKT and MAIT cell development using single cell transcriptomics data. Semin. Immunol. 2022, 60, 101658. [Google Scholar] [CrossRef]
- Van Kaer, L.; Parekh, V.V.; Wu, L. Invariant natural killer T cells: Bridging innate and adaptive immunity. Cell Tissue Res. 2011, 343, 43–55. [Google Scholar] [CrossRef]
- Li, J.H.; O’Sullivan, T.E. Back to the Future: Spatiotemporal Determinants of NK Cell Antitumor Function. Front. Immunol. 2021, 12, 816658. [Google Scholar] [CrossRef]
- Annunziato, F.; Romagnani, C.; Romagnani, S. The 3 major types of innate and adaptive cell-mediated effector immunity. J. Allergy Clin. Immunol. 2015, 135, 626–635. [Google Scholar] [CrossRef]
- Ham, H.; Medlyn, M.; Billadeau, D.D. Locked and Loaded: Mechanisms Regulating Natural Killer Cell Lytic Granule Biogenesis and Release. Front. Immunol. 2022, 13, 871106. [Google Scholar] [CrossRef] [PubMed]
- Harly, C.; Robert, J.; Legoux, F.; Lantz, O. γδ T, NKT, and MAIT Cells During Evolution: Redundancy or Specialized Functions? J. Immunol. 2022, 209, 217–225. [Google Scholar] [CrossRef] [PubMed]
- Ioannidis, M.; Cerundolo, V.; Salio, M. The Immune Modulating Properties of Mucosal-Associated Invariant T Cells. Front. Immunol. 2020, 11, 1556. [Google Scholar] [CrossRef] [PubMed]
- Pinco, P.; Facciotti, F. Unconventional T Cells’ Role in Cancer: Unlocking Their Hidden Potential to Guide Tumor Immunity and Therapy. Cells 2025, 14, 720. [Google Scholar] [CrossRef]
- Laub, A.; Rodrigues de Almeida, N.; Huang, S. Unconventional T cells in anti-cancer immunity. Front. Immunol. 2025, 16, 1618393. [Google Scholar] [CrossRef]
- Makkouk, A.; Yang, X.C.; Barca, T.; Lucas, A.; Turkoz, M.; Wong, J.T.S.; Nishimoto, K.P.; Brodey, M.M.; Tabrizizad, M.; Gundurao, S.R.Y.; et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J. Immunother. Cancer 2021, 9, e003441. [Google Scholar] [CrossRef]
- Cieslak, S.G.; Shahbazi, R. Gamma delta T cells and their immunotherapeutic potential in cancer. Biomark. Res. 2025, 13, 51. [Google Scholar] [CrossRef]
- Silva-Santos, B.; Serre, K.; Norell, H. γδ T cells in cancer. Nat. Rev. Immunol. 2015, 15, 683–691. [Google Scholar] [CrossRef]
- Gentles, A.J.; Newman, A.M.; Liu, C.L.; Bratman, S.V.; Feng, W.; Kim, D.; Nair, V.S.; Xu, Y.; Khuong, A.; Hoang, C.D. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 2015, 21, 938–945. [Google Scholar] [CrossRef]
- Sugimoto, C.; Fujita, H.; Wakao, H. Harnessing the Power of Mucosal-Associated Invariant T (MAIT) Cells in Cancer Cell Therapy. Biomedicines 2022, 10, 3160. [Google Scholar] [CrossRef]
- Anderson, A.C.; Joller, N.; Kuchroo, V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016, 44, 989–1004. [Google Scholar] [CrossRef] [PubMed]
- Jiang, W.; He, Y.; He, W.; Wu, G.; Zhou, X.; Sheng, Q.; Zhong, W.; Lu, Y.; Ding, Y.; Lu, Q.; et al. Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy. Front. Immunol. 2021, 11, 622509. [Google Scholar] [CrossRef] [PubMed]
- Chen, D.; Guo, Y.; Jiang, J.; Wu, P.; Zhang, T.; Wei, Q.; Huang, J.; Wu, D. γδ T cell exhaustion: Opportunities for intervention. J. Leukoc. Biol. 2022, 112, 1669–1676. [Google Scholar] [CrossRef] [PubMed]
- Shen, H.; Gu, J.; Xiao, H.; Liang, S.; Yang, E.; Yang, R.; Huang, D.; Chen, C.; Wang, F.; Shen, L. Selective Destruction of Interleukin 23–Induced Expansion of a Major Antigen–Specific γδ T-Cell Subset in Patients with Tuberculosis. J. Infect. Dis. 2017, 215, 420–430. [Google Scholar] [CrossRef]
- de Visser, K.E.; Joyce, J.A. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023, 41, 374–403. [Google Scholar] [CrossRef]
- Rafia, C.; Loizeau, C.; Renoult, O.; Harly, C.; Pecqueur, C.; Joalland, N.; Scotet, E. The antitumor activity of human Vγ9Vδ2 T cells is impaired by TGF-β through significant phenotype, transcriptomic and metabolic changes. Front. Immunol. 2023, 13, 1066336. [Google Scholar] [CrossRef]
- Mbongue, J.C.; Nicholas, D.A.; Torrez, T.W.; Kim, N.S.; Firek, A.F.; Langridge, W.H. The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity. Vaccines 2015, 3, 703–729. [Google Scholar] [CrossRef]
- Alshaker, H.A.; Matalka, K.Z. IFN-γ, IL-17 and TGF-β involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors. Cancer Cell Int. 2011, 11, 33. [Google Scholar] [CrossRef]
- Kuen, D.S.; Kim, B.S.; Chung, Y. IL-17-Producing Cells in Tumor Immunity: Friends or Foes? Immune Netw. 2020, 20, e6. [Google Scholar] [CrossRef]
- Mi, C.; Liu, S.; Chen, Z. Redefining hepatocellular carcinoma treatment: Nanotechnology meets tumor immune microenvironment. J. Drug Target. 2025, 33, 1125–1144. [Google Scholar] [CrossRef] [PubMed]
- Whyte, C.E. Chemokine-Mediated Control of Immunity to Tumours and Infectious Pathogens. Ph.D. Thesis, University of Adelaide, Adelaide, Australia, 2018. [Google Scholar]
- Jafarzadeh, L.; Masoumi, E.; Fallah-Mehrjardi, K.; Mirzaei, H.R.; Hadjati, J. Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward. Front. Immunol. 2020, 11, 702. [Google Scholar] [CrossRef] [PubMed]
- López-Cantillo, G.; Urueña, C.; Camacho, B.A.; Ramírez-Segura, C. CAR-T Cell Performance: How to Improve Their Persistence? Front. Immunol. 2022, 13, 878209. [Google Scholar] [CrossRef] [PubMed]
- Sun, L.; Su, Y.; Jiao, A.; Wang, X.; Zhang, B. T cells in health and disease. Signal Transduct. Target. Ther. 2023, 8, 235. [Google Scholar] [CrossRef]
- Wittling, M.C.; Cole, A.C.; Brammer, B.; Diatikar, K.G.; Schmitt, N.C.; Paulos, C.M. Strategies for Improving CAR T Cell Persistence in Solid Tumors. Cancers 2024, 16, 2858. [Google Scholar] [CrossRef]
- Wang, H.; Kjer-Nielsen, L.; Shi, M.; D’Souza, C.; Pediongco, T.J.; Cao, H.; Kostenko, L.; Lim, X.Y.; Eckle, S.B.G.; Meehan, B.S.; et al. IL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection. Sci. Immunol. 2019, 4, eaaw0402. [Google Scholar] [CrossRef]
- Feng, B.; Bai, Z.; Zhou, X.; Zhao, Y.; Xie, Y.-Q.; Huang, X.; Liu, Y.; Enbar, T.; Li, R.; Wang, Y.; et al. The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 2024, 634, 712–720. [Google Scholar] [CrossRef]
- Chow, A.; Perica, K.; Klebanoff, C.A.; Wolchok, J.D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 2022, 19, 775–790. [Google Scholar] [CrossRef]
- Gohil, S.H.; Iorgulescu, J.B.; Braun, D.A.; Keskin, D.B.; Livak, K.J. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat. Rev. Clin. Oncol. 2021, 18, 244–256. [Google Scholar] [CrossRef]
- Zhang, H.; Shen, H.; Zhou, L.; Xie, L.; Kong, D.; Wang, H. Mucosal-Associated Invariant T Cells in the Digestive System: Defender or Destroyer? Cell. Mol. Gastroenterol. Hepatol. 2023, 15, 809–819. [Google Scholar] [CrossRef] [PubMed]
- Revesz, I.A.; Joyce, P.; Ebert, L.M.; Prestidge, C.A. Effective γδ T-cell clinical therapies: Current limitations and future perspectives for cancer immunotherapy. Clin. Transl. Immunol. 2024, 13, e1492. [Google Scholar] [CrossRef] [PubMed]
- Schamel, W.W.; Zintchenko, M.; Nguyen, T.; Fehse, B.; Briquez, P.S.; Minguet, S. The potential of γδ CAR and TRuC T cells: An unearthed treasure. Eur. J. Immunol. 2024, 54, e2451074. [Google Scholar] [CrossRef] [PubMed]
- Aoki, T.; Motohashi, S.; Koseki, H. Regeneration of invariant natural killer T (iNKT) cells: Application of iPSC technology for iNKT cell-targeted tumor immunotherapy. Inflamm. Regen. 2023, 43, 27. [Google Scholar] [CrossRef]
- Cochrane, R.W.; Robino, R.A.; Granger, B.; Allen, E.; Vaena, S.; Romeo, M.J.; de Cubas, A.A.; Berto, S.; Ferreira, L.M.R. High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells. Mol. Ther. Methods Clin. Dev. 2024, 32, 101385. [Google Scholar] [CrossRef]
- Vasic, D.; Lee, J.B.; Leung, Y.; Khatri, I.; Na, Y.; Abate-Daga, D.; Zhang, L. Allogeneic double-negative CAR-T cells inhibit tumor growth without off-tumor toxicities. Sci. Immunol. 2022, 7, eabl3642. [Google Scholar] [CrossRef]
- Lanza, R.; Russell, D.W.; Nagy, A. Engineering universal cells that evade immune detection. Nat. Rev. Immunol. 2019, 19, 723–733. [Google Scholar] [CrossRef]
- Pal, S.K.; Tran, B.; Haanen, J.; Hurwitz, M.E.; Sacher, A.; Tannir, N.M.; Budde, L.E.; Harrison, S.J.; Klobuch, S.; Patel, S.S.; et al. CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma. Cancer Discov. 2024, 14, 1176–1189. [Google Scholar] [CrossRef]
- Schaft, N.; Dörrie, J.; Schuler, G.; Schuler-Thurner, B.; Sallam, H.; Klein, S.; Eisenberg, G.; Frankenburg, S.; Lotem, M.; Khatib, A. The future of affordable cancer immunotherapy. Front. Immunol. 2023, 14, 1248867. [Google Scholar] [CrossRef]
- Depil, S.; Duchateau, P.; Grupp, S.A.; Mufti, G.; Poirot, L. ‘Off-the-shelf’ allogeneic CAR T cells: Development and challenges. Nat. Rev. Drug Discov. 2020, 19, 185–199. [Google Scholar] [CrossRef]
- Deseke, M.; Prinz, I. Ligand recognition by the γδ TCR and discrimination between homeostasis and stress conditions. Cell. Mol. Immunol. 2020, 17, 914–924. [Google Scholar] [CrossRef]
- Minculescu, L.; Marquart, H.V.; Ryder, L.P.; Andersen, N.S.; Schjoedt, I.; Friis, L.S.; Kornblit, B.T.; Petersen, S.L.; Haastrup, E.; Fischer-Nielsen, A.; et al. Improved Overall Survival, Relapse-Free-Survival, and Less Graft-vs.-Host-Disease in Patients With High Immune Reconstitution of TCR Gamma Delta Cells 2 Months After Allogeneic Stem Cell Transplantation. Front. Immunol. 2019, 10, 1997. [Google Scholar] [CrossRef]
- Rezvani, K.; Rouce, R.; Liu, E.; Shpall, E. Engineering Natural Killer Cells for Cancer Immunotherapy. Mol. Ther. 2017, 25, 1769–1781. [Google Scholar] [CrossRef]
- Shin, M.H.; Kim, J.; Lim, S.A.; Kim, J.; Kim, S.-J.; Lee, K.-M. NK Cell-Based Immunotherapies in Cancer. Immune Netw. 2020, 20, e14. [Google Scholar] [CrossRef]
- Look, A.; Burns, D.; Tews, I.; Roghanian, A.; Mansour, S. Towards a better understanding of human iNKT cell subpopulations for improved clinical outcomes. Front. Immunol. 2023, 14, 1176724. [Google Scholar] [CrossRef]
- Labrijn, A.F.; Janmaat, M.L.; Reichert, J.M.; Parren, P.W.H.I. Bispecific antibodies: A mechanistic review of the pipeline. Nat. Rev. Drug Discov. 2019, 18, 585–608. [Google Scholar] [CrossRef] [PubMed]
- Topp, M.S.; Gökbuget, N.; Stein, A.S.; Zugmaier, G.; O’Brien, S.; Bargou, R.C.; Dombret, H.; Fielding, A.K.; Heffner, L.; Larson, R.A.; et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Oncol. 2015, 16, 57–66. [Google Scholar] [CrossRef] [PubMed]
- Brinkmann, U.; and Kontermann, R.E. The making of bispecific antibodies. mAbs 2017, 9, 182–212. [Google Scholar] [CrossRef] [PubMed]
- Hotta, A.; Lee, J. Hiding from allogeneic NK cells and macrophages by a synthetic receptor. Cell Stem Cell 2023, 30, 1393–1394. [Google Scholar] [CrossRef]
- Petrus-Reurer, S.; Romano, M.; Howlett, S.; Jones, J.L.; Lombardi, G.; Saeb-Parsy, K. Immunological considerations and challenges for regenerative cellular therapies. Commun. Biol. 2021, 4, 798. [Google Scholar] [CrossRef]
- Cartellieri, M.; Feldmann, A.; Koristka, S.; Arndt, C.; Loff, S.; Ehninger, A.; von Bonin, M.; Bejestani, E.P.; Ehninger, G.; Bachmann, M.P. Switching CAR T cells on and off: A novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016, 6, e458. [Google Scholar] [CrossRef]
- Mohty, R.; Lazaryan, A. “Off-The-Shelf” allogeneic chimeric antigen receptor T-cell therapy for B-cell malignancies: Current clinical evidence and challenges. Front. Oncol. 2024, 14, 1433432. [Google Scholar] [CrossRef]
- Shokati, A.; Sanjari-Pour, M.; Akhavan Rahnama, M.; Hoseinzadeh, S.; Vaezi, M.; Ahmadvand, M. Allogeneic CART progress: Platforms, current progress and limitations. Front. Immunol. 2025, 16, 1557157. [Google Scholar] [CrossRef] [PubMed]
- Caldwell, K.J.; Gottschalk, S.; Talleur, A.C. Allogeneic CAR Cell Therapy—More Than a Pipe Dream. Front. Immunol. 2021, 11, 618427. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; van den Brink, M.R.M. Allogeneic “Off-the-Shelf” CAR T cells: Challenges and advances. Best Pract. Res. Clin. Haematol. 2024, 37, 101566. [Google Scholar] [CrossRef] [PubMed]
- Shahid, S.; Prockop, S.E.; Flynn, G.C.; Mauguen, A.; White, C.O.; Bieler, J.; McAvoy, D.; Hosszu, K.; Cancio, M.I.; Jakubowski, A.A.; et al. Allogeneic off-the-shelf CAR T-cell therapy for relapsed or refractory B-cell malignancies. Blood Adv. 2025, 9, 1644–1657. [Google Scholar] [CrossRef]
- Ou, X.; Ma, Q.; Yin, W.; Ma, X.; He, Z. CRISPR/Cas9 Gene-Editing in Cancer Immunotherapy: Promoting the Present Revolution in Cancer Therapy and Exploring More. Front. Cell Dev. Biol. 2021, 9, 674467. [Google Scholar] [CrossRef]
- Rossetti, R.; Brand, H.; Lima, S.C.G.; Furtado, I.P.; Silveira, R.M.; Fantacini, D.M.C.; Covas, D.T.; de Souza, L.E.B. Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer. Immunother. Adv. 2022, 2, ltac005. [Google Scholar] [CrossRef]
- Aljabali, A.A.A.; Hamzat, Y.; Alqudah, A.; Alzoubi, L. Neoantigen vaccines: Advancing personalized cancer immunotherapy. Explor. Immunol. 2025, 5, 1003190. [Google Scholar] [CrossRef]
- Peng, H.; Li, L.; Zuo, C.; Chen, M.Y.; Zhang, X.; Myers, N.B.; Hogg, G.D.; DeNardo, D.G.; Goedegebuure, S.P.; Hawkins, W.G.; et al. Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer. Front. Immunol. 2022, 13, 1039226. [Google Scholar] [CrossRef]
- Wang, Y.; Han, J.; Wang, D.; Cai, M.; Xu, Y.; Hu, Y.; Chen, H.; He, W.; Zhang, J. Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer. Signal Transduct. Target. Ther. 2023, 8, 399. [Google Scholar] [CrossRef] [PubMed]
- Ribas, A.; Dummer, R.; Puzanov, I.; VanderWalde, A.; Andtbacka, R.H.I.; Michielin, O.; Olszanski, A.J.; Malvehy, J.; Cebon, J.; Fernandez, E.; et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell 2017, 170, 1109–1119.e10. [Google Scholar] [CrossRef] [PubMed]
- Rodrigo, J.P.; Sánchez-Canteli, M.; Otero-Rosales, M.; Martínez-Camblor, P.; Hermida-Prado, F.; García-Pedrero, J.M. Tumor mutational burden predictability in head and neck squamous cell carcinoma patients treated with immunotherapy: Systematic review and meta-analysis. J. Transl. Med. 2024, 22, 135. [Google Scholar] [CrossRef]
- Rahim, M.K.; Okholm, T.L.H.; Jones, K.B.; McCarthy, E.E.; Liu, C.C.; Yee, J.L.; Tamaki, S.J.; Marquez, D.M.; Tenvooren, I.; Wai, K.; et al. Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell 2023, 186, 1127–1143.e1118. [Google Scholar] [CrossRef]
- Li, C.; Guo, H.; Zhai, P.; Yan, M.; Liu, C.; Wang, X.; Shi, C.; Li, J.; Tong, T.; Zhang, Z.; et al. Spatial and Single-Cell Transcriptomics Reveal a Cancer-Associated Fibroblast Subset in HNSCC That Restricts Infiltration and Antitumor Activity of CD8+ T Cells. Cancer Res. 2024, 84, 258–275. [Google Scholar] [CrossRef]
- Bergamaschi, C.; Gaspar, M.; Ciucci, T.; Sitnikova, S.I.; Cayatte, C.; Pica, M.; Dovedi, S.J. Innovative strategies for T cell engagers for cancer immunotherapy. mAbs 2025, 17, 2531223. [Google Scholar] [CrossRef]
- Azar, F.; Deforges, J.; Demeusoit, C.; Kleinpeter, P.; Remy, C.; Silvestre, N.; Foloppe, J.; Fend, L.; Spring-Giusti, C.; Quéméneur, E.; et al. TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment. J. Immunother. Cancer 2024, 12, e009302. [Google Scholar] [CrossRef]
- Lausen, M.; Petersen, N.V.; Long, G.V.; Khattak, M.A.; Ascierto, P.A.; Queirolo, P.; Pavlidis, M.A.; Friis Thorsen, S.; Chisamore, M.J.; Kleine-Kohlbrecher, D.; et al. Immunogenicity of an AI-designed personalized neoantigen vaccine, EVX-01, in combination with anti-PD-1 therapy in patients with metastatic melanoma. J. Clin. Oncol. 2024, 42, 9561. [Google Scholar] [CrossRef]
- Long, G.V.; Ferrucci, P.F.; Khattak, A.; Meniawy, T.M.; Ott, P.A.; Chisamore, M.; Trolle, T.; Hyseni, A.; Heegaard, E. KEYNOTE—D36: Personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma. Future Oncol. 2022, 18, 3473–3480. [Google Scholar] [CrossRef]
- Cai, Y.; Chen, R.; Gao, S.; Li, W.; Liu, Y.; Su, G.; Song, M.; Jiang, M.; Jiang, C.; Zhang, X. Artificial intelligence applied in neoantigen identification facilitates personalized cancer immunotherapy. Front. Oncol. 2023, 12, 1054231. [Google Scholar] [CrossRef]
- Xie, J.; Luo, X.; Deng, X.; Tang, Y.; Tian, W.; Cheng, H.; Zhang, J.; Zou, Y.; Guo, Z.; Xie, X. Advances in artificial intelligence to predict cancer immunotherapy efficacy. Front. Immunol. 2023, 13, 1076883. [Google Scholar] [CrossRef]
- Khattak, M.A.A.; Ascierto, P.A.; Queirolo, P.; Chisamore, M.; Kleine-Kohlbrecher, D.; Lausen, M.; Viborg, N.; Pavlidis, M.A.; Andersen, R.O.; Jepsen, T.S.; et al. 1084P Phase II study of AI-designed personalized neoantigen cancer vaccine, EVX-01, in combination with pembrolizumab in advanced melanoma. Ann. Oncol. 2024, 35, S718–S719. [Google Scholar] [CrossRef]
- Kumar, A.; Dixit, S.; Srinivasan, K.M.D.; Vincent, P.M.D.R. Personalized cancer vaccine design using AI-powered technologies. Front. Immunol. 2024, 15, 1357217. [Google Scholar] [CrossRef] [PubMed]
- Li, D.; Li, X.; Zhou, W.-L.; Huang, Y.; Liang, X.; Jiang, L.; Yang, X.; Sun, J.; Li, Z.; Han, W.-D.; et al. Genetically engineered T cells for cancer immunotherapy. Signal Transduct. Target. Ther. 2019, 4, 35. [Google Scholar] [CrossRef] [PubMed]
- Hemminki, O.; dos Santos, J.M.; Hemminki, A. Oncolytic viruses for cancer immunotherapy. J. Hematol. Oncol. 2020, 13, 84. [Google Scholar] [CrossRef] [PubMed]
- Pandya, A.; Shah, Y.; Kothari, N.; Postwala, H.; Shah, A.; Parekh, P.; Chorawala, M.R. The future of cancer immunotherapy: DNA vaccines leading the way. Med. Oncol. 2023, 40, 200. [Google Scholar] [CrossRef]
- Shiravand, Y.; Khodadadi, F.; Kashani, S.M.A.; Hosseini-Fard, S.R.; Hosseini, S.; Sadeghirad, H.; Ladwa, R.; O’Byrne, K.; Kulasinghe, A. Immune Checkpoint Inhibitors in Cancer Therapy. Curr. Oncol. 2022, 29, 3044–3060. [Google Scholar] [CrossRef]
- Chehelgerdi, M.; Chehelgerdi, M. The use of RNA-based treatments in the field of cancer immunotherapy. Mol. Cancer 2023, 22, 106. [Google Scholar] [CrossRef]
- Fesnak, A.D.; June, C.H.; Levine, B.L. Engineered T cells: The promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 2016, 16, 566–581. [Google Scholar] [CrossRef]
- Shafer, P.; Kelly, L.M.; Hoyos, V. Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects. Front. Immunol. 2022, 13, 835762. [Google Scholar] [CrossRef]
- Rath, J.A.; Arber, C. Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy. Cells 2020, 9, 1485. [Google Scholar] [CrossRef]
- Ghazi, B.; El Ghanmi, A.; Kandoussi, S.; Ghouzlani, A.; Badou, A. CAR T-cells for colorectal cancer immunotherapy: Ready to go? Front. Immunol. 2022, 13, 978195. [Google Scholar] [CrossRef]
- Malviya, M.; Aretz, Z.E.H.; Molvi, Z.; Lee, J.; Pierre, S.; Wallisch, P.; Dao, T.; Scheinberg, D.A. Challenges and solutions for therapeutic TCR-based agents. Immunol. Rev. 2023, 320, 58–82. [Google Scholar] [CrossRef]
- Sterner, R.C.; Sterner, R.M. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J. 2021, 11, 69. [Google Scholar] [CrossRef]
- Chapuis, A.G.; Egan, D.N.; Bar, M.; Schmitt, T.M.; McAfee, M.S.; Paulson, K.G.; Voillet, V.; Gottardo, R.; Ragnarsson, G.B.; Bleakley, M.; et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat. Med. 2019, 25, 1064–1072. [Google Scholar] [CrossRef] [PubMed]
- Lowery, F.J.; Krishna, S.; Yossef, R.; Parikh, N.B.; Chatani, P.D.; Zacharakis, N.; Parkhurst, M.R.; Levin, N.; Sindiri, S.; Sachs, A.; et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science 2022, 375, 877–884. [Google Scholar] [CrossRef] [PubMed]
- Nagarsheth, N.B.; Norberg, S.M.; Sinkoe, A.L.; Adhikary, S.; Meyer, T.J.; Lack, J.B.; Warner, A.C.; Schweitzer, C.; Doran, S.L.; Korrapati, S.; et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 2021, 27, 419–425. [Google Scholar] [CrossRef] [PubMed]
- Sharpe, M.; Mount, N. Genetically modified T cells in cancer therapy: Opportunities and challenges. Dis. Models Mech. 2015, 8, 337–350. [Google Scholar] [CrossRef]
- Zhang, Y.; Liu, Z.; Wei, W.; Li, Y. TCR engineered T cells for solid tumor immunotherapy. Exp. Hematol. Oncol. 2022, 11, 38. [Google Scholar] [CrossRef]
- Balyan, R.; Gautam, N.; Gascoigne, N.R.J. The Ups and Downs of Metabolism during the Lifespan of a T Cell. Int. J. Mol. Sci. 2020, 21, 7972. [Google Scholar] [CrossRef]
- Zhao, S.; Peralta, R.M.; Avina-Ochoa, N.; Delgoffe, G.M.; Kaech, S.M. Metabolic regulation of T cells in the tumor microenvironment by nutrient availability and diet. Semin. Immunol. 2021, 52, 101485. [Google Scholar] [CrossRef]
- Chang, C.H.; Qiu, J.; O’Sullivan, D.; Buck, M.D.; Noguchi, T.; Curtis, J.D.; Chen, Q.; Gindin, M.; Gubin, M.M.; Van Der Windt, G.J.; et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 2015, 162, 1229–1241. [Google Scholar] [CrossRef]
- Liu, L.; Hao, Z.; Yang, X.; Li, Y.; Wang, S.; Li, L. Metabolic reprogramming in T cell senescence: A novel strategy for cancer immunotherapy. Cell Death Discov. 2025, 11, 161. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Kurupati, R.; Liu, L.; Zhou, X.Y.; Zhang, G.; Hudaihed, A.; Filisio, F.; Giles-Davis, W.; Xu, X.; Karakousis, G.C.; et al. Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 2017, 32, 377–391.e379. [Google Scholar] [CrossRef] [PubMed]
- Tang, Y.; Chen, Z.; Zuo, Q.; Kang, Y. Regulation of CD8+ T cells by lipid metabolism in cancer progression. Cell. Mol. Immunol. 2024, 21, 1215–1230. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Chaudhary, O.; Rodríguez-Morales, P.; Sun, X.; Chen, D.; Zappasodi, R.; Xu, Z.; Pinto, A.F.M.; Williams, A.; Schulze, I.; et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 2021, 54, 1561–1577.e1567. [Google Scholar] [CrossRef]
- Cao, J.; Liao, S.; Zeng, F.; Liao, Q.; Luo, G.; Zhou, Y. Effects of altered glycolysis levels on CD8+ T cell activation and function. Cell Death Dis. 2023, 14, 407. [Google Scholar] [CrossRef]
- Fan, H.; Wu, Y.; Yu, S.; Li, X.; Wang, A.; Wang, S.; Chen, W.; Lu, Y. Critical role of mTOR in regulating aerobic glycolysis in carcinogenesis (Review). Int. J. Oncol. 2021, 58, 9–19. [Google Scholar] [CrossRef]
- Panwar, V.; Singh, A.; Bhatt, M.; Tonk, R.K.; Azizov, S.; Raza, A.S.; Sengupta, S.; Kumar, D.; Garg, M. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct. Target. Ther. 2023, 8, 375. [Google Scholar] [CrossRef]
- Araki, K.; Turner, A.P.; Shaffer, V.O.; Gangappa, S.; Keller, S.A.; Bachmann, M.F.; Larsen, C.P.; Ahmed, R. mTOR regulates memory CD8 T-cell differentiation. Nature 2009, 460, 108–112. [Google Scholar] [CrossRef]
- Mafi, S.; Mansoori, B.; Taeb, S.; Sadeghi, H.; Abbasi, R.; Cho, W.C.; Rostamzadeh, D. mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment. Front. Immunol. 2022, 12, 774103. [Google Scholar] [CrossRef]
- Yang, M.-Q.; Zhang, S.-L.; Sun, L.; Huang, L.-T.; Yu, J.; Zhang, J.-H.; Tian, Y.; Han, C.-B.; Ma, J.-T. Targeting mitochondria: Restoring the antitumor efficacy of exhausted T cells. Mol. Cancer 2024, 23, 260. [Google Scholar] [CrossRef]
- Li, H.; Zhao, A.; Li, M.; Shi, L.; Han, Q.; Hou, Z. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy. Front. Immunol. 2022, 13, 1046755. [Google Scholar] [CrossRef] [PubMed]
- Cherry, E.M.; Abbott, D.; Amaya, M.; McMahon, C.; Schwartz, M.; Rosser, J.; Sato, A.; Schowinsky, J.; Inguva, A.; Minhajuddin, M.; et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv. 2021, 5, 5565–5573. [Google Scholar] [CrossRef] [PubMed]
- Kaminskas, E.; Farrell, A.; Abraham, S.; Baird, A.; Hsieh, L.-S.; Lee, S.-L.; Leighton, J.K.; Patel, H.; Rahman, A.; Sridhara, R.; et al. Approval Summary: Azacitidine for Treatment of Myelodysplastic Syndrome Subtypes. Clin. Cancer Res. 2005, 11, 3604–3608. [Google Scholar] [CrossRef]
- Roussos Torres, E.T.; Rafie, C.; Wang, C.; Lim, D.; Brufsky, A.; LoRusso, P.; Eder, J.P.; Chung, V.; Downs, M.; Geare, M.; et al. Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844). Clin. Cancer Res. 2021, 27, 5828–5837. [Google Scholar] [CrossRef] [PubMed]
- Hellmann, M.D.; Jänne, P.A.; Opyrchal, M.; Hafez, N.; Raez, L.E.; Gabrilovich, D.I.; Wang, F.; Trepel, J.B.; Lee, M.-J.; Yuno, A.; et al. Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti–PD-(L)1 Therapy. Clin. Cancer Res. 2021, 27, 1019–1028. [Google Scholar] [CrossRef]
- Wang, N.; Li, Y.; Wang, Y.; Wang, W. Integration of multi-omics profiling reveals an epigenetic-based molecular classification of lung adenocarcinoma: Implications for drug sensitivity and immunotherapy response prediction. Front. Pharmacol. 2025, 16, 1540477. [Google Scholar] [CrossRef]
- Polverino, A.; Sorrentino, P.; Pesoli, M.; Mandolesi, L. Nutrition and cognition across the lifetime: An overview on epigenetic mechanisms. AIMS Neurosci. 2021, 8, 448–476. [Google Scholar] [CrossRef]
- Venditti, S.; Verdone, L.; Reale, A.; Vetriani, V.; Caserta, M.; Zampieri, M. Molecules of Silence: Effects of Meditation on Gene Expression and Epigenetics. Front. Psychol. 2020, 11, 1767. [Google Scholar] [CrossRef]
- Zadorozhna, M.; Mangieri, D. Mechanisms of Chemopreventive and Therapeutic Proprieties of Ginger Extracts in Cancer. Int. J. Mol. Sci. 2021, 22, 6599. [Google Scholar] [CrossRef]
- Isola, S.; Gammeri, L.; Furci, F.; Gangemi, S.; Pioggia, G.; Allegra, A. Vitamin C Supplementation in the Treatment of Autoimmune and Onco-Hematological Diseases: From Prophylaxis to Adjuvant Therapy. Int. J. Mol. Sci. 2024, 25, 7284. [Google Scholar] [CrossRef]
- Huang, S.-H.; Wu, C.-H.; Chen, S.-J.; Sytwu, H.-K.; Lin, G.-J. Immunomodulatory effects and potential clinical applications of dimethyl sulfoxide. Immunobiology 2020, 225, 151906. [Google Scholar] [CrossRef]
- Bailey, S.R.; Maus, M.V. Gene editing for immune cell therapies. Nat. Biotechnol. 2019, 37, 1425–1434. [Google Scholar] [CrossRef] [PubMed]
- Feng, X.; Li, Z.; Liu, Y.; Chen, D.; Zhou, Z. CRISPR/Cas9 technology for advancements in cancer immunotherapy: From uncovering regulatory mechanisms to therapeutic applications. Exp. Hematol. Oncol. 2024, 13, 102. [Google Scholar] [CrossRef] [PubMed]
- Srour, S.A.; Chahoud, J.; Drakaki, A.; Curti, B.D.; Pal, S.; Tang, L.; Prashad, S.; Atwell, J.; Williams, C.; Ghatta, S.; et al. 322 ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC): Updated safety and efficacy from the phase 1 TRAVERSE multicenter study. J. Immunother. Cancer 2024, 12, A373. [Google Scholar] [CrossRef]
- Lee, N.K.; Chang, J.W. Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation. Ann. Lab. Med. 2024, 44, 314–323. [Google Scholar] [CrossRef]
- DiRaimondo, T.; Budimir, N.; Shenhav, S.; Wu, H.; Cicchini, V.; Jocic, R.; Ma, L.; Roup, F.; Campbell, C.; Caffaro, C.; et al. 1325 Preclinical activity and safety profile of JANX007, a novel PSMA-targeting tumor-activated T Cell engager for treatment of metastatic castration-resistant prostate cancer. J. Immunother. Cancer 2022, 10, A1376. [Google Scholar] [CrossRef]
- Champiat, S.; Lebbe, C.; Baurain, J.F.; Italiano, A.; Sakkal, M.; Spring-Giusti, C.; Stojkowitz, N.; Brandely, M.; Sadoun, A.; Ropenga, A.; et al. 1024P Initial clinical results of BT-001, an oncolytic virus expressing an anti-CTLA4 mAb, administered as single agent and in combination with pembrolizumab in patients with advanced solid tumors. Ann. Oncol. 2024, 35, S692. [Google Scholar] [CrossRef]
- Olawade, D.B.; Clement David-Olawade, A.; Adereni, T.; Egbon, E.; Teke, J.; Boussios, S. Integrating AI into Cancer Immunotherapy—A Narrative Review of Current Applications and Future Directions. Diseases 2025, 13, 24. [Google Scholar] [CrossRef]
- Sharma, P.; Hu-Lieskovan, S.; Wargo, J.A.; Ribas, A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017, 168, 707–723. [Google Scholar] [CrossRef]
- Lancellotti, C.; Cancian, P.; Savevski, V.; Kotha, S.R.R.; Fraggetta, F.; Graziano, P.; Di Tommaso, L. Artificial Intelligence & Tissue Biomarkers: Advantages, Risks and Perspectives for Pathology. Cells 2021, 10, 787. [Google Scholar] [CrossRef]
- Martins, J.; Magalhães, C.; Rocha, M.; Osório, N.S. Machine Learning-Enhanced T Cell Neoepitope Discovery for Immunotherapy Design. Cancer Inform. 2019, 18, 1176935119852081. [Google Scholar] [CrossRef]
Modality | Translational Challenges | Engineering Strategies | Clinical Status | References |
---|---|---|---|---|
CAR-MAIT Cells | Limited ex vivo expansion; low frequency in peripheral blood; MR1 restriction | Feeder-free expansion using 5-OP-RU and IL-7/IL-23; CRISPR-mediated CAR knock-in with inducible promoters | Preclinical studies | [15,26,102] |
CAR-γδ T Cells | Short in vivo persistence; donor variability; functional exhaustion | IL-15 co-expression; PD-1 knockout; Vδ1 subset selection; CXCR3 chemokine receptor engineering; metabolic support | Phase I trials are ongoing, ADI-270 (renal cell carcinoma) and KB-GDT-01 (metastatic non-small-cell lung cancer) received FDA Fast Track status | [30,79,103,104] |
CAR-iNKT Cells | Low abundance in humans; need for sustained effector function | Use of IL-15-expressing CARs; CD62L+ donor selection; IL-12 polarization; scalable iPSC-derived iNKT generation | Phase I trial completed in neuroblastoma (25% ORR, no DLTs); not yet FDA-approved | [19,21,22,105] |
CAR-Tregs | In vivo instability; risk of off-target suppression; antigen specificity | FoxP3-stabilized CAR constructs; antigen-specific Treg targeting; local delivery using synthetic biology control systems | Preclinical studies are promising for autoimmunity and transplantation | [17,32,106] |
Double-Negative T Cells | Low abundance; insufficient expansion protocols; unclear clinical niche | Leverage TNFα-JAK1-ICAM-1 cytotoxic axis; GvHD-free cytotoxic approaches for AML | Preclinical only: functional studies in AML mouse models | [24,31,107] |
Universal CAR Platforms | Immunogenicity of allogeneic cells: risk of rejection and poor persistence | CRISPR-mediated HLA-I/II knockout; CD47 overexpression (“do not eat me” signal); modular switchable CAR constructs for universal applicability | Early-phase clinical trials: hypoimmunogenic CAR-Ts show early safety data | [18,108,109] |
Feature | Autologous Immune Cell Therapies | Allogeneic “Off-the-Shelf” Immune Cell Therapies | References |
---|---|---|---|
Source of Cells | Patient-derived (e.g., T cells, NK cells) | Healthy donors or universal engineered cell lines | [123,124,125] |
Manufacturing Time | Several weeks due to patient-specific cell collection and expansion | Pre-manufactured and cryopreserved; ready for immediate use | [123,126,127] |
Scalability | Limited by patient-to-patient production | Highly scalable; batch production for multiple patients | [124,125,126] |
Cost | High due to individualized manufacturing | Potentially lower due to economies of scale | [123,125,126,127] |
Consistency and Quality Control | Variable, dependent on patient health and immune status | More uniform product with standardized quality | [123,125,127] |
Risk of Immune Rejection | Minimal, as cells are self-derived | Higher risk; requires gene-editing to remove alloreactive components (e.g., TCR knockout, HLA engineering) | [123,124,126,128] |
Graft-versus-Host Disease (GvHD) Risk | Low (self-cells) | Higher risk unless modified (e.g., using gene editing or NK cells/γδ T cells) | [123,124,125,126] |
Time to Treatment | Delayed (weeks for manufacturing) | Immediate (on-demand use) | [123,127] |
Applications in Current Trials | CAR-T (CD19, BCMA), TILs | Universal CAR-T (UCART19, ALLO-501), CAR-NK, engineered γδ T cells | [123,126,127,128] |
Integration with Gene Editing | Limited (focus on persistence, safety switches) | Essential (to overcome host rejection, enhance tumor targeting, and remove alloreactive responses) | [126,128] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Alturki, M.; Alshehri, A.A.; Aldossary, A.M.; Fallatah, M.M.; Almughem, F.A.; Al Fayez, N.; Majrashi, M.A.; Alradwan, I.A.; Alkhrayef, M.; Alomary, M.N.; et al. Unconventional Immunotherapies in Cancer: Opportunities and Challenges. Pharmaceuticals 2025, 18, 1154. https://doi.org/10.3390/ph18081154
Alturki M, Alshehri AA, Aldossary AM, Fallatah MM, Almughem FA, Al Fayez N, Majrashi MA, Alradwan IA, Alkhrayef M, Alomary MN, et al. Unconventional Immunotherapies in Cancer: Opportunities and Challenges. Pharmaceuticals. 2025; 18(8):1154. https://doi.org/10.3390/ph18081154
Chicago/Turabian StyleAlturki, Meshael, Abdullah A. Alshehri, Ahmad M. Aldossary, Mohannad M. Fallatah, Fahad A. Almughem, Nojoud Al Fayez, Majed A. Majrashi, Ibrahim A. Alradwan, Mohammad Alkhrayef, Mohammad N. Alomary, and et al. 2025. "Unconventional Immunotherapies in Cancer: Opportunities and Challenges" Pharmaceuticals 18, no. 8: 1154. https://doi.org/10.3390/ph18081154
APA StyleAlturki, M., Alshehri, A. A., Aldossary, A. M., Fallatah, M. M., Almughem, F. A., Al Fayez, N., Majrashi, M. A., Alradwan, I. A., Alkhrayef, M., Alomary, M. N., & Tawfik, E. A. (2025). Unconventional Immunotherapies in Cancer: Opportunities and Challenges. Pharmaceuticals, 18(8), 1154. https://doi.org/10.3390/ph18081154