The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of metabolic alterations of glycolysis, glutaminolysis, and lipogenesis, processes essential to the survival of bulk and CSC populations. Over the past decade, the Wnt pathway has also been shown to regulate the tumor microenvironment (TME) and anti-cancer immunity. Wnt ligands released by tumor cells in the TME facilitate the immune evasion of cancer cells and hamper immunotherapy. In this review, we illustrate the role of the canonical Wnt/β-catenin pathway in cancer metabolism and immunity to explore the potential therapeutic approach of targeting Wnt signaling from a metabolic and immunological perspective.

With improved understanding of the immunogenicity of triple-negative breast cancer (TNBC), immunotherapy has emerged as a promising candidate to treat this lethal disease owing to the lack of specific targets and effective treatments. While immune checkpoint inhibition (ICI) has been effectively used in immunotherapy for several types of solid tumor, monotherapies targeting programmed death 1 (PD-1), its ligand PD-L1, or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have shown little efficacy for TNBC patients. Over the past few years, various therapeutic candidates have been reviewed, attempting to improve ICI efficacy on TNBC through combinatorial treatment. In this review, we describe the clinical limitations of ICI and illustrate candidates from an immunological, pharmacological, and metabolic perspective that may potentiate therapy to improve the outcomes of TNBC patients.

Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.

Triple-negative breast cancer (TNBC) is the most aggressive and refractory subtype of breast cancer, often occurring in younger patients with poor clinical prognosis. Given the current lack of specific targets for effective intervention, the development of better treatment strategies remains an unmet medical need. Over the last decade, the field of extracellular vesicles (EVs) has grown tremendously, offering immense potential for clinical diagnosis/prognosis and therapeutic applications. While TNBC-EVs have been shown to play an important role in tumorigenesis, chemoresistance and metastasis, they could be repurposed as potential biomarkers for TNBC diagnosis and prognosis. Furthermore, EVs from various cell types can be utilized as nanoscale drug delivery systems (NDDS) for TNBC treatment. Remarkably, EVs generated from specific immune cell subsets have been shown to delay solid tumour growth and reduce tumour burden, suggesting a new immunotherapy approach for TNBC. Intrinsically, EVs can cross the blood–brain barrier (BBB), which holds great potential to treat the brain metastases diagnosed in one third of TNBC patients that remains a substantial clinical challenge. In this review, we present the most recent applications of EVs in TNBC as diagnostic/prognostic biomarkers, nanoscale drug delivery systems and immunotherapeutic agents, as well as discuss the associated challenges and future directions of EVs in cancer immunotherapy.