Background: Chemoresistance constitutes a significant clinical hurdle in the management of triple-negative breast cancer (TNBC), a highly aggressive and molecularly heterogeneous subtype lacking established targeted therapies. TNBC’s ability to hijack diverse signalling pathways further complicates therapeutic intervention.
Objective: We aimed to investigate the role of a novel phosphorylation-dependent molecular switch on Protein Kinase C delta (PKCδ) in driving chemoresistance in TNBC, and to explore its impact on tumour–immune dynamics.
Methods: We identified a phospho-regulated form of PKCδ that promotes proliferation and drug resistance in human TNBC cell lines. The switch was detected in ~30% of TNBC patient tumour samples. To study its functional role in vivo, we employed a syngeneic TNBC mouse model expressing high levels of either wild-type or non-phosphorylatable PKCδ. Mice were treated with Cisplatin or Docetaxel, and tumour response and immune landscape were assessed.
Results: Tumours expressing the phosphorylated PKCδ switch displayed resistance to both chemotherapeutic agents. In contrast, tumours harbouring the non-phosphorylatable mutant showed a significantly reduced growth rate upon treatment. Remarkably, even in the absence of chemotherapy, these tumours exhibited slower growth, suggesting an endogenous immune-mediated response. Flow cytometry and immunophenotyping revealed distinct immune signatures between the two groups, including alterations in immune cell subsets within the tumour microenvironment and spleen.
Conclusion: This study identifies a novel PKCδ-mediated molecular switch that promotes chemoresistance and modulates the immune landscape in TNBC. These findings support its potential as a predictive biomarker of drug response and a therapeutic target for combination strategies aimed at restoring chemosensitivity.