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Publications

Journal Article Review Ppublish

PubMed: 41284319 DOI: 10.1080/07853890.2025.2593198

Dual targeting of PD-1/PD-L1 and iL-33/ST2 signalling pathways: a promising approach in breast cancer immunotherapy.

Ann Med 57(1):2593198

Authors: Milan Jovanovic, Nevena Gajovic, Miodrag Jocic, Marina Jovanovic, Milena Jurisevic, Ivan Jovanovic

Affiliations

  • Department of Abdominal surgery, Military Medical Academy, Belgrade, Serbia. Medical Faculty of the Military Medical, Academy University of Defense, Belgrade, Serbia.
  • Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.
  • Medical Faculty of the Military Medical, Academy University of Defense, Belgrade, Serbia.
  • Institute for Transfusiology and Haemobiology, Military Medical Academy, Belgrade, Serbia.
  • Department of Otorhinolaryngology, University of Kragujevac, Kragujevac, Serbia.
  • Department of Pharmacy, University of Kragujevac, Kragujevac, Serbia.
  • Department of Medicine, University of East Sarajevo, Foca, Bosnia and Herzegovina.

Abstract

INTRODUCTION

The immune checkpoint axis PD-1/PD-L1 is a cornerstone of cancer immunotherapy. However, its efficacy in breast cancer is often limited by a complex and immunosuppressive tumour microenvironment (TME). The IL-33/ST2 signalling pathway, a key player in type 2 inflammation, is increasingly recognized for its pro-tumoral roles in various cancers, contributing to immune evasion and metastasis. This review explores the synergistic potential of combining PD-1/PD-L1 blockade with IL-33/ST2 inhibition to overcome therapeutic resistance and enhance anti-tumour immunity in breast cancer.

METHODS

Current literature on the PD-1/PD-L1 and IL-33/ST2 pathways in breast cancer progression was synthesized, focusing on their mechanisms of immune suppression and TME modulation. It examines preclinical and clinical data on the individual and combined therapeutic strategies targeting these pathways.

RESULTS

Evidence suggests that IL-33 signalling promotes a suppressive TME by recruiting regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, which can limit the effectiveness of PD-1/PD-L1 inhibitors. Conversely, blocking the IL-33/ST2 pathway has been shown to reprogram the TME, leading to increased infiltration of cytotoxic T lymphocytes and enhanced anti-tumour responses. Therefore, a dual-targeting approach is proposed to simultaneously disarm these two distinct but cooperative immune evasion mechanisms.

CONCLUSION

Dual blockade of PD-1/PD-L1 and IL-33/ST2 signalling pathways represents a novel and promising strategy to enhance the efficacy of immunotherapy in breast cancer. This approach has the potential to revert the immunosuppressive TME, leading to more durable and robust anti-tumour responses. Further research is warranted to validate this hypothesis and translate it into effective clinical trials.

MeSH

Cells, Myeloid-Derived Suppressor Cells, Breast Neoplasms, Neoplasms, Immunotherapy, Breast, Therapeutics, Interleukin-33, Immune Evasion