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Targeting CB1 and TRPM8 receptors to counteract CD8+ T cell exhaustion
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  • Published: 10 April 2026

Targeting CB1 and TRPM8 receptors to counteract CD8+ T cell exhaustion

  • Adel Mohammadzadeh1,2,
  • Sahand Moazzendizzaji3,
  • Aliasghar Tabatabaei Mohammadi4,
  • Afsaneh Ahmadi5,
  • Rahim Mahmodlou6 &
  • …
  • Ali Akbar Pourfathollah7,8 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Drug discovery
  • Immunology

Abstract

The prolonged interaction between the immune system and tumor antigens can result in T cell exhaustion. Extensive research has been conducted on strategies to reactivate exhausted T cells within the tumor microenvironment. However the exact contribution of the endocannabinoid system (ECS) and nociceptors in regulating CD8+ T cells within the framework of cancer-related inflammation has not been thoroughly studied. This study investigated the use of a TRPM8 antagonist (RQ-00203078), a selective cannabinoid receptor 1 (CB1) antagonist (AM251), and alpelisib (BYL-719) to control CD8+ T cell exhaustion. Our findings showed that administration of the CB1 antagonist AM251, either alone or in combination with alpelisib, significantly reduced the expression of PD-1 and Lag-3 on CD8+ T cells. Interestingly, treatment with the TRPM8 antagonist led to a notable increase in PD-1 expression on CD8+ T cells. These findings suggest that the decreased expression of inhibitory receptors on CD8+ T cells after treatment with the CB1 antagonist whether alone or with alpelisib and TRPM8 highlights the potential of ECS as a promising therapeutic target in cancer treatment.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials, and can also be obtained from the corresponding author upon request.

Abbreviations

CNS:

Central nervous system

ECS:

Endocannabinoid system

CB1:

Cannabinoid receptor 1

CB1 ant:

Cannabinoid receptor 1 antagonist

TRPM8:

Transient receptor potential cation channel subfamily M member 8

TRPM8 ant:

Transient receptor potential cation channel subfamily M member 8 antagonist

PI3K:

Phosphoinositide 3-kinase

PD-1:

Programmed cell death protein 1

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen 4

Lag-3:

Lymphocyte activation gene 3

TIM-3:

T cell immunoglobulin domain and mucin domain

BTLA:

B- and T-lymphocyte attenuator

TIGIT:

T cell immunoreceptor with immunoglobulin and ITIM domain

AEA:

Anandamide

2-AG:

2-Arachidonoylglycerol

ICBs:

Immune checkpoint inhibitors

IHC:

Immunohistochemistry

References

  1. Giles, J. R., Globig, A. M., Kaech, S. M. & Wherry, E. J. CD8(+) T cells in the cancer-immunity cycle. Immunity 56, 2231–2253. https://doi.org/10.1016/j.immuni.2023.09.005 (2023).

    Google Scholar 

  2. Napolitano, F. et al. CD8+ T cells in the tumor microenvironment modulate response to endocrine therapy in breast cancer. J. Clin. Invest. https://doi.org/10.1172/jci188458 (2025).

    Google Scholar 

  3. Han, K.-C. et al. Streamlined selection of cancer antigens for vaccine development through integrative multi-omics and high-content cell imaging. Sci. Rep. 10, 5885. https://doi.org/10.1038/s41598-020-62244-z (2020).

    Google Scholar 

  4. Hosonuma, M. & Yoshimura, K. Association between pH regulation of the tumor microenvironment and immunological state. Front. Oncol. 13, 1175563. https://doi.org/10.3389/fonc.2023.1175563 (2023).

    Google Scholar 

  5. Yang, W. et al. T-cell infiltration and its regulatory mechanisms in cancers: Insights at single-cell resolution. J. Exp. Clin. Cancer Res. 43, 38. https://doi.org/10.1186/s13046-024-02960-w (2024).

    Google Scholar 

  6. Li, X. et al. Targeting tumor innervation: Premises, promises, and challenges. Cell Death Discov. 8, 131. https://doi.org/10.1038/s41420-022-00930-9 (2022).

    Google Scholar 

  7. Mardelle, U., Bretaud, N., Daher, C. & Feuillet, V. From pain to tumor immunity: Influence of peripheral sensory neurons in cancer. Front. Immunol. 15, 1335387. https://doi.org/10.3389/fimmu.2024.1335387 (2024).

    Google Scholar 

  8. Matsueda, S., Chen, L., Li, H., Yao, H. & Yu, F. Recent clinical researches and technological development in TIL therapy. Cancer Immunol. Immunother. 73, 232. https://doi.org/10.1007/s00262-024-03793-4 (2024).

    Google Scholar 

  9. Koh, C.-H., Lee, S., Kwak, M., Kim, B.-S. & Chung, Y. CD8 T-cell subsets: Heterogeneity, functions, and therapeutic potential. Exp. Mol. Med. 55, 2287–2299. https://doi.org/10.1038/s12276-023-01105-x (2023).

    Google Scholar 

  10. Huang, Y., Jia, A., Wang, Y. & Liu, G. CD8+ T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy. Immunology 168, 30–48. https://doi.org/10.1111/imm.13588 (2023).

    Google Scholar 

  11. Turnis, M. E., Andrews, L. P. & Vignali, D. A. A. Inhibitory receptors as targets for cancer immunotherapy. Eur. J. Immunol. 45, 1892–1905. https://doi.org/10.1002/eji.201344413 (2015).

    Google Scholar 

  12. Xiang, S., Li, S. & Xu, J. Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy. Clin. Transl. Med. 15, e70345. https://doi.org/10.1002/ctm2.70345 (2025).

    Google Scholar 

  13. Cheng, L. et al. Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: A real-world comparison. Mol. Cancer 23, 77. https://doi.org/10.1186/s12943-024-01956-6 (2024).

    Google Scholar 

  14. Park, Y.-J., Kuen, D.-S. & Chung, Y. Future prospects of immune checkpoint blockade in cancer: From response prediction to overcoming resistance. Exp. Mol. Med. 50, 1–13. https://doi.org/10.1038/s12276-018-0130-1 (2018).

    Google Scholar 

  15. Yin, X., He, L. & Guo, Z. T-cell exhaustion in CAR-T-cell therapy and strategies to overcome it. Immunology 169, 400–411. https://doi.org/10.1111/imm.13642 (2023).

    Google Scholar 

  16. Kouro, T., Himuro, H. & Sasada, T. Exhaustion of CAR T cells: Potential causes and solutions. J. Transl. Med. 20, 239. https://doi.org/10.1186/s12967-022-03442-3 (2022).

    Google Scholar 

  17. Sousa-Valente, J., Andreou, A. P., Urban, L. & Nagy, I. Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics. Br. J. Pharmacol. 171, 2508–2527. https://doi.org/10.1111/bph.12532 (2014).

    Google Scholar 

  18. Koivisto, A.-P., Belvisi, M. G., Gaudet, R. & Szallasi, A. Advances in TRP channel drug discovery: From target validation to clinical studies. Nat. Rev. Drug Discov. 21, 41–59. https://doi.org/10.1038/s41573-021-00268-4 (2022).

    Google Scholar 

  19. Zhang, M. et al. TRP (transient receptor potential) ion channel family: Structures, biological functions and therapeutic interventions for diseases. Signal Transduct. Target. Ther. 8, 261. https://doi.org/10.1038/s41392-023-01464-x (2023).

    Google Scholar 

  20. Pertusa, M., Solorza, J. & Madrid, R. Molecular determinants of TRPM8 function: Key clues for a cool modulation. Front. Pharmacol. 14, 1213337. https://doi.org/10.3389/fphar.2023.1213337 (2023).

    Google Scholar 

  21. Turcotte, C., Chouinard, F., Lefebvre, J. S. & Flamand, N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J. Leukoc. Biol. 97, 1049–1070. https://doi.org/10.1189/jlb.3RU0115-021R (2015).

    Google Scholar 

  22. Lutz, B. Neurobiology of cannabinoid receptor signaling. Dialogues Clin. Neurosci. 22, 207–222. https://doi.org/10.31887/DCNS.2020.22.3/blutz (2020).

    Google Scholar 

  23. Hinz, B. & Ramer, R. Cannabinoids as anticancer drugs: Current status of preclinical research. Br. J. Cancer. 127, 1–13. https://doi.org/10.1038/s41416-022-01727-4 (2022).

    Google Scholar 

  24. Wang, D. et al. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res. 68, 6468–6476. https://doi.org/10.1158/0008-5472.Can-08-0896 (2008).

    Google Scholar 

  25. Rahaman, O. & Ganguly, D. Endocannabinoids in immune regulation and immunopathologies. Immunology 164, 242–252. https://doi.org/10.1111/imm.13378 (2021).

    Google Scholar 

  26. Tanaka, K. et al. Gene expression of the endocannabinoid system in endometrium through menstrual cycle. Sci. Rep. 12, 9400. https://doi.org/10.1038/s41598-022-13488-4 (2022).

    Google Scholar 

  27. Wong, T.-S. et al. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Signal. Transduct. Target. Ther. 8, 177. https://doi.org/10.1038/s41392-023-01427-2 (2023).

    Google Scholar 

  28. Khunluck, T. et al. Activation of cannabinoid receptors in breast cancer cells improves osteoblast viability in cancer-bone interaction model while reducing breast cancer cell survival and migration. Sci. Rep. 12, 7398. https://doi.org/10.1038/s41598-022-11116-9 (2022).

    Google Scholar 

  29. Di Donato, M. et al. Therapeutic potential of TRPM8 antagonists in prostate cancer. Sci. Rep. 11, 23232. https://doi.org/10.1038/s41598-021-02675-4 (2021).

    Google Scholar 

  30. Chodon, D. et al. Estrogen regulation of TRPM8 expression in breast cancer cells. BMC Cancer 10, 212. https://doi.org/10.1186/1471-2407-10-212 (2010).

    Google Scholar 

  31. Chakravarti, B., Ravi, J. & Ganju, R. K. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 5, 5852–5872 (2014).

    Google Scholar 

  32. Mattioli, R. et al. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol. Aspects Med. 93, 101205. https://doi.org/10.1016/j.mam.2023.101205 (2023).

    Google Scholar 

  33. Khan, S. U., Fatima, K., Aisha, S. & Malik, F. Unveiling the mechanisms and challenges of cancer drug resistance. Cell. Commun. Signal. 22, 109. https://doi.org/10.1186/s12964-023-01302-1 (2024).

    Google Scholar 

  34. Emerling, B. M. & Akcakanat, A. Targeting PI3K/mTOR signaling in cancer. Cancer Res. 71, 7351–7359. https://doi.org/10.1158/0008-5472.Can-11-1699 (2011).

    Google Scholar 

  35. Zhang, H. P. et al. PI3K/AKT/mTOR signaling pathway: An important driver and therapeutic target in triple-negative breast cancer. Breast Cancer 31, 539–551. https://doi.org/10.1007/s12282-024-01567-5 (2024).

    Google Scholar 

  36. Takata, H. & Trautmann, L. Transforming dysfunctional CD8+ T cells into natural controller-like CD8+ T cells: Can TCF-1 be the magic wand?. J. Clin. Invest. https://doi.org/10.1172/jci160474 (2022).

    Google Scholar 

  37. Zhang, J., Lyu, T., Cao, Y. & Feng, H. Role of TCF-1 in differentiation, exhaustion, and memory of CD8+ T cells: A review. FASEB J. 35, e21549. https://doi.org/10.1096/fj.202002566R (2021).

    Google Scholar 

  38. Zuniga, E. I. & Harker, J. A. T-cell exhaustion due to persistent antigen: Quantity not quality?. Eur. J. Immunol. 42, 2285–2289. https://doi.org/10.1002/eji.201242852 (2012).

    Google Scholar 

  39. Șerban, M., Toader, C. & Covache-Busuioc, R.-A. The endocannabinoid system in human disease: Molecular signaling, receptor pharmacology, and therapeutic innovation. Int. J. Mol. Sci. 26, 11132 (2025).

    Google Scholar 

  40. Chow, A., Perica, K., Klebanoff, C. A. & Wolchok, J. D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 19, 775–790. https://doi.org/10.1038/s41571-022-00689-z (2022).

    Google Scholar 

  41. Schillebeeckx, I. et al. T cell subtype profiling measures exhaustion and predicts anti-PD-1 response. Sci. Rep. 12, 1342. https://doi.org/10.1038/s41598-022-05474-7 (2022).

    Google Scholar 

  42. Woroniecka, K. et al. T-cell exhaustion signatures vary with tumor type and are severe in Glioblastoma. Clin. Cancer Res. 24, 4175–4186. https://doi.org/10.1158/1078-0432.Ccr-17-1846 (2018).

    Google Scholar 

  43. Poorebrahim, M. et al. Counteracting CAR T cell dysfunction. Oncogene 40, 421–435. https://doi.org/10.1038/s41388-020-01501-x (2021).

    Google Scholar 

  44. Catakovic, K., Klieser, E., Neureiter, D. & Geisberger, R. T cell exhaustion: From pathophysiological basics to tumor immunotherapy. Cell Commun. Signal. 15, 1. https://doi.org/10.1186/s12964-016-0160-z (2017).

    Google Scholar 

  45. Huang, A. C. & Zappasodi, R. A decade of checkpoint blockade immunotherapy in melanoma: Understanding the molecular basis for immune sensitivity and resistance. Nat. Immunol. 23, 660–670. https://doi.org/10.1038/s41590-022-01141-1 (2022).

    Google Scholar 

  46. Sun, Q. et al. Immune checkpoint therapy for solid tumours: Clinical dilemmas and future trends. Signal Transduct. Target. Ther. 8, 320. https://doi.org/10.1038/s41392-023-01522-4 (2023).

    Google Scholar 

  47. Catozzi, S. et al. Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An in-depth chronotherapeutic study. Eur. J. Cancer https://doi.org/10.1016/j.ejca.2024.113571 (2024).

    Google Scholar 

  48. Farina, A. et al. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol. 23, 81–94. https://doi.org/10.1016/S1474-4422(23)00369-1 (2024).

    Google Scholar 

  49. Schnell, A., Bod, L., Madi, A. & Kuchroo, V. K. The yin and yang of co-inhibitory receptors: Toward anti-tumor immunity without autoimmunity. Cell Res. 30, 285–299. https://doi.org/10.1038/s41422-020-0277-x (2020).

    Google Scholar 

  50. Pinho-Ribeiro, F. A., Verri, W. A. Jr. & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19. https://doi.org/10.1016/j.it.2016.10.001 (2017).

    Google Scholar 

  51. Pan, T. et al. Pan-cancer analyses reveal the genetic and pharmacogenomic landscape of transient receptor potential channels. Npj. Genom. Med. 7, 32. https://doi.org/10.1038/s41525-022-00304-1 (2022).

    Google Scholar 

  52. Wong, C. et al. 4E-BP1–dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling. Sci. Adv. 9, eadh9603. https://doi.org/10.1126/sciadv.adh9603 (2023).

    Google Scholar 

  53. Géranton, S. M. et al. A Rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J. Neurosci. 29, 15017–15027. https://doi.org/10.1523/jneurosci.3451-09.2009 (2009).

    Google Scholar 

  54. Wei, F. et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc. Natl. Acad. Sci. USA 110, E2480-2489. https://doi.org/10.1073/pnas.1305394110 (2013).

    Google Scholar 

  55. Huang, H. et al. The immunomodulatory effects of endocrine therapy in breast cancer. J. Exp. Clin. Cancer Res. 40, 19. https://doi.org/10.1186/s13046-020-01788-4 (2021).

    Google Scholar 

  56. Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195-211.e110. https://doi.org/10.1016/j.immuni.2018.12.021 (2019).

    Google Scholar 

  57. Ochoa, S. V., Casas, Z., Albarracín, S. L., Sutachan, J. J. & Torres, Y. P. Therapeutic potential of TRPM8 channels in cancer treatment. Front. Pharmacol. 14, 1098448. https://doi.org/10.3389/fphar.2023.1098448 (2023).

    Google Scholar 

  58. Pagano, E. et al. TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/β-catenin signalling. Br. J. Pharmacol. 180, 235–251. https://doi.org/10.1111/bph.15960 (2023).

    Google Scholar 

  59. Grolez, G. P. et al. Encapsulation of a TRPM8 agonist, WS12, in lipid nanocapsules potentiates PC3 prostate cancer cell migration inhibition through channel activation. Sci. Rep. 9, 7926. https://doi.org/10.1038/s41598-019-44452-4 (2019).

    Google Scholar 

  60. Le Fèvre, C. et al. Ellipsoid calculations versus manual tumor delineations for glioblastoma tumor volume evaluation. Sci. Rep. 12, 10502. https://doi.org/10.1038/s41598-022-13739-4 (2022).

    Google Scholar 

  61. Percie du Sert, N. et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS. Biol. 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410 (2020).

    Google Scholar 

  62. Djoufack-Momo, S. M., Amparan, A. A., Grunden, B. & Boivin, G. P. Evaluation of carbon dioxide dissipation within a euthanasia chamber. J. Am. Assoc. Lab. Anim. Sci. 53, 404–407 (2014).

    Google Scholar 

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Funding

The authors did not receive any financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran

    Adel Mohammadzadeh

  2. Department of Immunology and Genetics, Urmia University of Medical Sciences, Urmia, Iran

    Adel Mohammadzadeh

  3. Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Sahand Moazzendizzaji

  4. School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

    Aliasghar Tabatabaei Mohammadi

  5. Department of Infectious Diseases, Immigrant Health Clinic, Copenhagen University Hospital, Hvidovre, Denmark

    Afsaneh Ahmadi

  6. Department of General Surgery, Urmia University of Medical Sciences, Urmia, Iran

    Rahim Mahmodlou

  7. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Ali Akbar Pourfathollah

  8. Iranian Blood Transfusion Organization, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

    Ali Akbar Pourfathollah

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Contributions

A.M. conceptualized, designed, and conducted the majority of the experiments, performed statistical analyses, and authored the manuscript. S.D. made significant contributions to cell culture, cell processing, and animal handling tasks. A.T.M. assisted with software applications, analysis, visualization of data, and manuscript writing. A.A. provided consultation on drug preparations and partially drafted the manuscript related to the drug discussions and writing. R.M., a breast cancer surgeon, and A.A.P. offered valuable insights and critical revision feedback that enhanced the results and discussion sections. All authors participated in the editing process and approved the final manuscript.

Corresponding author

Correspondence to Adel Mohammadzadeh.

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Competing interests

The authors declare no competing interests.

Ethics statement

To establish the 4T1-induced breast cancer model, it was confirmed that all animal care and experimental procedures conducted in this study adhered to the ethical guidelines approved by Urmia University of Medical Sciences, in alignment with ARRIVE guidelines (ARRIVE 2.0)61. All authors acknowledge the ethical considerations relevant to this manuscript. Ethical approval for this research was obtained from the Ethics Committee of Urmia University of Medical Sciences under approval code [IR.UMSU.AEC.1401.004]. Mice were maintained under standard housing conditions with a controlled temperature of 22°C, following a 12-h light/dark cycle. Food and water were available at all times, and appropriate air conditioning was implemented to minimize potential harm or distress. All necessary measures and precautions were employed to ensure the well-being of the animals. At the conclusion of the experiment, in accordance with IACUC guidelines, all euthanasia procedures for the mice were conducted using carbon dioxide (CO2) gas at a flow rate of 3 L/min until respiration ceased62. Prior to this procedure, the animal received anesthesia to minimize distress, which involved administering a mixture of ketamine (80 mg/kg) and xylazine (5 mg/kg) via intraperitoneal injection. Euthanasia was subsequently performed using CO₂ asphyxiation, followed by the cervical dislocation method, which involved placing a pen directly behind the ears at the base of the skull and, while lifting the base of the tail, dislocating the cervical vertebrae. In this study, female BALB/c mice, weighing between 21 and 23 g and aged 6–8 weeks, were obtained from the Pasteur Institute in Tehran, Iran. Upon reaching the logarithmic growth phase, 4T1 cell lines were trypsinized (using Gibco), resuspended, and a suspension containing 1 × 105 4T1 cells in 100 μL of sterile phosphate-buffered saline (PBS) was injected into the mammary fat pad of the mice. Eight days post-implantation, the mice were evaluated for tumor growth and were randomly assigned to treatment and control groups. The experimental groups consisted of eight categories: Control or Untreated, Alp (Alpelisib treated), TRPM8 ant (TRPM8 antagonist treated), CB1 ant (CB1 antagonist treated), Alp/CB1 ant (Alpelisib & CB1 antagonist treated), TRPM8/CB1 ant (TRPM8 & CB1 antagonist treated), Alp/TRPM8 ant (Alpelisib & TRPM8 antagonist treated), and Alp/CB1/TRPM8 ant (Alpelisib & CB1 & TRPM8 antagonist treated), with n = 5 mice in each group. In total, n = 50 mice were utilized for tumor induction, resulting in n = 4–5 mice in each experimental group. Mice that did not develop a tumor mass or exhibited a tumor mass significantly larger than the others by day 8 of induction were excluded from the study. Additionally, 4–5 mice were randomly allocated to each cage (Large cage Size (W × L × H), 7.5″ × 11.75″ × 5″) for each experimental group.

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Mohammadzadeh, A., Moazzendizzaji, S., Mohammadi, A.T. et al. Targeting CB1 and TRPM8 receptors to counteract CD8+ T cell exhaustion. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46794-2

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  • Received: 13 November 2025

  • Accepted: 27 March 2026

  • Published: 10 April 2026

  • DOI: https://doi.org/10.1038/s41598-026-46794-2

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Keywords

  • Neuro-immune interaction
  • CD8+ T cell exhaustion
  • PD-1 and Lag-3
  • Alpelisib
  • CB1 and TRPM8 antagonists
  • Nociceptors
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