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

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.

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.

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.

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.