Cancer immunotherapy and cardiovascular side-effects: from treatment modalities to the use of the preventive effect of antihypertensive drugs

Abstract

Cancer treatment regimens are significantly more intricate than commonly perceived. Nonetheless, both immunotherapy and chemotherapy may produce adverse consequences. Immunotherapy represents a significant advancement in the battle against cancer; nonetheless, it is not devoid of challenges. This research elucidates the mechanisms underlying immunotherapy-induced cardiovascular damage, highlighting the significant role of immune regulators, such as soluble urokinase plasminogen activator receptor (suPAR), in inducing vascular leakage. We also examine the role of matrix metalloproteinase (MMP14/15) in this process, and antigens associated with cardiovascular illness and malignancies, including native proteins, mutated tumor antigens, and viral components. Besides, we studied predictive biomarkers, such as circulating T-cell populations associated with the probability of myocarditis. We discuss treatment approaches and strategies to mitigate these issues, particularly through the use of antihypertensive medications to reduce their impact. Losartan alters the tumor microenvironment (TME) to improve immunotherapy. It restores immune effector cells in triple-negative breast cancer (TNBC), overcomes resistance in unresponsive tumors, and modifies TMEs’ immune system suppression in ovarian cancer and melanoma. It is important to note that its effects differ by cancer kind. It may promote fibrosarcoma tumor growth and improve cholangiocarcinoma treatment. This shows that losartan’s dangers in cancer treatment should be carefully considered and that more research is needed. This suggests that there must be careful consideration of the potential risks associated with losartan use in cancer treatment and underscores the requirement for additional research on this topic. This study may enhance our comprehension and management of cardiovascular adverse effects in cancer immunotherapy by integrating novel insights on immunological predictors and vascular dysfunction. Experts assert that oncology programs must provide and promote continuous monitoring of cardiac health for breast cancer patients. To mitigate the risk of cardiovascular disease in this demographic, comprehensive patient care must be administered.

Keywords

cardiovascular diseases (CVD) / immune checkpoint inhibitors (ICIs) / immunotherapy / cancer / side-effects

References

[1] Khan M, Maker AV, Jain S. The Evolution of Cancer Immunotherapy. Vaccines (Basel). 2021; 9: 614. [DOI] [PubMed] [PMC]

[2] Lowery FJ, Krishna S, Yossef R, Parikh NB, Chatani PD, Zacharakis N, et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science. 2022; 375: 877-84. [DOI] [PubMed] [PMC]

[3] Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2022; 10: 1367-401. [DOI] [PubMed] [PMC]

[4] Roy R, Singh SK, Misra S. Advancements in Cancer Immunotherapies. Vaccines (Basel). 2022; 11: 59. [DOI] [PubMed] [PMC]

[5] Turcotte S, Donia M, Gastman B, Besser M, Brown R, Coukos G, et al. Art of TIL immunotherapy: SITC’s perspective on demystifying a complex treatment. J Immunother Cancer. 2025; 13: e010207. [DOI] [PubMed] [PMC]

[6] Chun KS, Kim DH, Raut PK, Surh YJ. Anticancer natural products targeting immune checkpoint protein network. Semin Cancer Biol. 2022; 86: 1008-32. [DOI] [PubMed]

[7] Iwasaki A, Omer SB. Why and How Vaccines Work. Cell. 2020; 183: 290-5. [DOI] [PubMed] [PMC]

[8] Ackerman RS, Muncey AR, Aldawoodi NN, Kotha R, Getting REG. Cancer Immunotherapies: What the Perioperative Physician Needs to Know. Curr Oncol Rep. 2022; 24: 399-414. [DOI] [PubMed] [PMC]

[9] Rafikov R, Rischard F, Vasilyev M, Varghese MV, Yuan JX, Desai AA, et al. Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex. Transl Res. 2022; 247: 1-18. [DOI] [PubMed] [PMC]

[10] Zahavi D, Weiner L. Monoclonal Antibodies in Cancer Therapy. Antibodies (Basel). 2020; 9: 34. [DOI] [PubMed] [PMC]

[11] Schaft N, Dörrie J, Schuler G, Schuler-Thurner B, Sallam H, Klein S, et al. The future of affordable cancer immunotherapy. Front Immunol. 2023; 14: 1248867. [DOI] [PubMed] [PMC]

[12] Tan S, Day D, Nicholls SJ, Segelov E. Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: JACC: CardioOncology State-of-the-Art Review . JACC CardioOncol. 2022; 4: 579-97. [DOI] [PubMed] [PMC]

[13] Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007; 121: 1-14. [DOI] [PubMed] [PMC]

[14] Corthay A. Does the immune system naturally protect against cancer? Front Immunol. 2014; 5: 197. [DOI] [PubMed] [PMC]

[15] Fuge O, Vasdev N, Allchorne P, Green JS. Immunotherapy for bladder cancer. Res Rep Urol. 2015; 7: 65-79. [DOI] [PubMed] [PMC]

[16] Parvez A, Choudhary F, Mudgal P, Khan R, Qureshi KA, Farooqi H, et al. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front Immunol. 2023; 14: 1296341. [DOI] [PubMed] [PMC]

[17] Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017; 44: 136-40. [DOI] [PubMed] [PMC]

[18] Zaenker P, Gray ES, Ziman MR. Autoantibody Production in Cancer——The Humoral Immune Response toward Autologous Antigens in Cancer Patients. Autoimmun Rev. 2016; 15: 477-83. [DOI] [PubMed]

[19] Strzelec M, Detka J, Mieszczak P, Sobocińska MK, Majka M. Immunomodulation-a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol. 2023; 14: 1127704. [DOI] [PubMed] [PMC]

[20] Quinteros DA, Bermúdez JM, Ravetti S, Cid A, Allemandi DA, Palma SD : Therapeutic use of monoclonal antibodies: general aspects and challenges for drug delivery. Nanostructures for drug delivery. 2017: 807-33. [DOI]

[21] Ling SP, Ming LC, Dhaliwal JS, Gupta M, Ardianto C, Goh KW, et al. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers (Basel). 2022; 14: 5205. [DOI] [PubMed] [PMC]

[22] Fernández-Galván A, Rodríguez-Jiménez P, González-Sixto B, Abalde-Pintos MT, Butrón-Bris B. Topical and Intralesional Immunotherapy for the Management of Basal Cell Carcinoma. Cancers (Basel). 2024; 16: 2135. [DOI] [PubMed] [PMC]

[23] Gatwood K, Mahmoudjafari Z, Baer B, Pak S, Lee B, Kim H, et al. Outpatient CAR T-Cell Therapy as Standard of Care: Current Perspectives and Considerations. Clin Hematol Int. 2024; 6: 11-20. [DOI] [PubMed] [PMC]

[24] Cha JH, Chan LC, Song MS, Hung MC. New Approaches on Cancer Immunotherapy. Cold Spring Harb Perspect Med. 2020; 10: a036863. [DOI] [PubMed] [PMC]

[25] Yu S, Wang Y, He P, Shao B, Liu F, Xiang Z, et al. Effective Combinations of Immunotherapy and Radiotherapy for Cancer Treatment. Front Oncol. 2022; 12: 809304. [DOI] [PubMed] [PMC]

[26] Sambi M, Bagheri L, Szewczuk MR. Current Challenges in Cancer Immunotherapy: Multimodal Approaches to Improve Efficacy and Patient Response Rates. J Oncol. 2019; 2019: 4508794. [DOI] [PubMed] [PMC]

[27] Maria-Ferreira D, Fernandes ES, Machado-Souza C, Schiebel CS, Dos Santos Maia AC, Barbosa LV. Editorial: Reducing adverse effects of cancer immunotherapy. Front Immunol. 2024; 15: 1368496. [DOI] [PubMed] [PMC]

[28] Aleman BM, Moser EC, Nuver J, Suter TM, Maraldo MV, Specht L, et al. Cardiovascular disease after cancer therapy. EJC Suppl. 2014; 12: 18-28. [DOI] [PubMed] [PMC]

[29] Blaes A, Konety S, Hurley P. Cardiovascular Complications of Hematopoietic Stem Cell Transplantation. Curr Treat Options Cardiovasc Med. 2016; 18: 25. [DOI] [PubMed] [PMC]

[30] Herbach E, O’Rorke MA, Carnahan RM, McDowell BD, Allen B, Grumbach I, et al. Cardiac Adverse Events Associated With Chemo-Radiation Versus Chemotherapy for Resectable Stage III Non-Small-Cell Lung Cancer: A Surveillance, Epidemiology and End Results-Medicare Study. J Am Heart Assoc. 2022; 11: e027288. [DOI] [PubMed] [PMC]

[31] Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. ; ESMO Guidelines Committee. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020; 31: 171-90. [DOI] [PubMed] [PMC]

[32] Okwundu N, Grossman D, Hu-Lieskovan S, Grossmann KF, Swami U. The dark side of immunotherapy. Ann Transl Med. 2021; 9: 1041. [DOI] [PubMed] [PMC]

[33] Carrillo-Salinas FJ, Ngwenyama N, Anastasiou M, Kaur K, Alcaide P. Heart Inflammation: Immune Cell Roles and Roads to the Heart. Am J Pathol. 2019; 189: 1482-94. [DOI] [PubMed] [PMC]

[34] Schultz JC, Hilliard AA, Cooper LT Jr, Rihal CS. Diagnosis and Treatment of Viral Myocarditis. Mayo Clin Proc. 2009; 84: 1001-9. [DOI] [PubMed] [PMC]

[35] Pandolfi F, Cianci R, Pagliari D, Casciano F, Bagalà C, Astone A, et al. The Immune Response to Tumors as a Tool toward Immunotherapy. Clin Dev Immunol. 2011; 2011: 894704. [DOI] [PubMed] [PMC]

[36] Wang L, Zhang Y, Zhang SY. Immunotherapy for the rheumatoid arthritis-associated coronary artery disease: promise and future. Chin Med J (Engl). 2019; 132: 2972-83. [DOI] [PubMed] [PMC]

[37] Jyothi Ramachandran Nair DP, Zachariah S, Scollan D, Shaikh A. Myocarditis: A Rare Complication of Immune Checkpoint Inhibitor Therapy. Cureus. 2024; 16: e60459. [DOI] [PubMed] [PMC]

[38] Frascaro F, Bianchi N, Sanguettoli F, Marchini F, Meossi S, Zanarelli L, et al. Immune Checkpoint Inhibitors-Associated Myocarditis: Diagnosis, Treatment and Current Status on Rechallenge. J Clin Med. 2023; 12: 7737. [DOI] [PubMed] [PMC]

[39] Zotova L. Immune Checkpoint Inhibitors-Related Myocarditis: A Review of Reported Clinical Cases. Diagnostics (Basel). 2023; 13: 1243. [DOI] [PubMed] [PMC]

[40] Blum SM, Zlotoff DA, Smith NP, Kernin IJ, Ramesh S, Zubiri L, et al. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature. 2024; 636: 215-23. [DOI] [PubMed]

[41] Kichloo A, Albosta M, Dahiya D, Guidi JC, Aljadah M, Singh J, et al. Systemic adverse effects and toxicities associated with immunotherapy: A review. World J Clin Oncol. 2021; 12: 150-63. [DOI] [PubMed] [PMC]

[42] Goldman M, Lucke-Wold B, Martinez-Sosa M, Katz J, Mehkri Y, Valisno J, et al. Steroid utility, immunotherapy, and brain tumor management: an update on conflicting therapies. Explor Target Antitumor Ther. 2022; 3: 659-75. [DOI] [PubMed] [PMC]

[43] Asiedu-Gyekye IJ, Antwi DA. Does losartan prevent cerebral edema? A preliminary study using a vascular compartment model. Med Sci Monit. 2003; 9: BR127-30. [PubMed]

[44] Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers. J Cereb Blood Flow Metab. 2016; 36: 1481-507. [DOI] [PubMed] [PMC]

[45] Datta M, Chatterjee S, Perez EM, Gritsch S, Roberge S, Duquette M, et al. Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models. Proc Natl Acad Sci U S A. 2023; 120: e2219199120. [DOI] [PubMed] [PMC]

[46] Yang J, Chen M, Li R, Sun Y, Ye P, Fang K, et al. A responsive cocktail nano-strategy breaking the immune excluded state enhances immunotherapy for triple negative breast cancer. Nanoscale. 2025; 17: 4610-23. [DOI]

[47] Hou X, Shen Y, Huang B, Li Q, Li S, Jiang T, et al. Losartan-based nanocomposite hydrogel overcomes chemo-immunotherapy resistance by remodeling tumor mechanical microenvironment. J Nanobiotechnology. 2024; 22: 667. [DOI] [PubMed] [PMC]

[48] Sun Y, Yin Z, Li S, Wu L, Zhang Y, Zhao Y, et al. Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer. Br J Cancer. 2024; 131: 1683-93. [DOI] [PubMed] [PMC]

[49] da Silva WN, Carvalho Costa PA, Scalzo Júnior SRA, Ferreira HAS, Prazeres PHDM, Campos CLV, et al. Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression. Int J Nanomedicine. 2024; 19: 2655-73. [DOI] [PubMed] [PMC]

[50] Sun J, Zhang C, Su X, Zhou H, Zhou S, Jiang M, et al. Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy. J Orthop Surg Res. 2024; 19: 147. [DOI] [PubMed] [PMC]

[51] Liu Z, Wang Z, Zhang Z, Zhang Z, Qi X, Zhu H, et al. Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic “Cold”-“Hot” Tumor Transformations. Nano Lett. 2024; 24: 1510-21. [DOI] [PubMed]

[52] Ramzy A, Soliman AH, Hassanein SI, Sebak AA. Multitarget, multiagent PLGA nanoparticles for simultaneous tumor eradication and TME remodeling in a melanoma mouse model. Drug Deliv Transl Res. 2024; 14: 491-509. [DOI] [PubMed] [PMC]

[53] Puopolo T, Li H, Gutkowski J, Cai A, Seeram NP, Ma H, et al. Establishment of Human PD-1/PD-L1 Blockade Assay Based on Surface Plasmon Resonance (SPR) Biosensor. Bio Protoc. 2023; 13: e4765. [DOI] [PubMed] [PMC]

[54] Li X, Luo X, Hu S. Modulating the tumor microenvironment improves antitumor effect of anti-PD-L1 mAb in breast cancer. Bioimpacts. 2023; 13: 89-96. [DOI] [PubMed] [PMC]

[55] Li X, Luo Y, Huang Z, Wang Y, Wu J, Zhou S. Multifunctional Liposomes Remodeling Tumor Immune Microenvironment for Tumor Chemoimmunotherapy. Small Methods. 2023; 7: e2201327. [DOI] [PubMed]

[56] Ammons DT, Guth A, Rozental AJ, Kurihara J, Marolf AJ, Chow L, et al. Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses. Cancer Res Commun. 2022; 2: 1657-67. [DOI] [PubMed] [PMC]

[57] Li Q, Chang Z, Wang T, Liu B, Wang X, Ge XY, et al. Synergy of Losartan and chemotherapy for patients with cholangiocarcinoma: A propensity score-matched analysis. Front Oncol. 2022; 12: 989080. [DOI] [PubMed] [PMC]

[58] Zhao Q, He X, Qin X, Liu Y, Jiang H, Wang J, et al. Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer. Front Immunol. 2022; 13: 938439. [DOI] [PubMed] [PMC]

[59] Regan DP, Coy JW, Chahal KK, Chow L, Kurihara JN, Guth AM, et al. The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment. J Immunol. 2019; 202: 3087-102. [DOI] [PubMed] [PMC]

[60] Sabaté-Ortega J, Teixidor-Vilà E, Sais È, Hernandez-Martínez A, Montañés-Ferrer C, Coma N, et al. Cardiovascular toxicity induced by immunotherapy in non-small cell lung cancer: a systematic review and meta-analysis of observational studies. Front Oncol. 2025; 15: 1528950. [DOI] [PubMed] [PMC]

[61] Yamani N, Ahmed A, Ruiz G, Zubair A, Arif F, Mookadam F. Immune checkpoint inhibitor-induced cardiotoxicity in patients with lung cancer: a systematic review and meta-analysis. Cardiooncology. 2024; 10: 37. [DOI] [PubMed] [PMC]

[62] Xavier CB, Lopes CDH, Harada G, Peres EDB, Katz A, Jardim DL. Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis. Transl Oncol. 2022; 19: 101383. [DOI] [PubMed] [PMC]

[63] Zhou F, Liu G, Zhang S, Luo C, Hu S, Wan S, et al. Cardiotoxicity in cancer immunotherapy: a systematic review and global meta-analysis. J Transl Med. 2025; 23: 718. [DOI] [PubMed] [PMC]

[64] Alam A, Devi S, Hashmi S. Critical Challenges in Cancer Immunotherapy and Cardiac Health. Curr Cardiol Rev. 2025; 21: 13. [DOI] [PubMed]