Overcoming immunotherapy resistance in triple-negative breast cancer: a critical review of mast cell plasticity, metabolic reprogramming, and organoid models.

Immunotherapy resistance in triple-negative breast cancer (TNBC) remains a critical clinical challenge. This review synthesizes and critically evaluates current evidence on two interconnected mechanisms that have emerged from recent research: the functional plasticity of mast cells (MCs) and metabolic reprogramming. Far from being mere allergic effectors, MCs exhibit high phenotypic diversity, with antigen-presenting MCs (apMCs) representing a unique subset identified in recent studies capable of priming anti-tumor T cell responses. A landmark phase 2 trial has demonstrated that modulation of apMCs can enhance responses to anti-PD-1 therapy in patients with ICI-refractory TNBC. However, within the TNBC TIME, metabolic dysregulation-characterized by glycolytic flux, lactate accumulation, and lipid alterations-skews MCs toward immunosuppressive phenotypes and suppresses apMC function. Published studies have documented that this bidirectional crosstalk forms a vicious cycle that sustains immune evasion and limits the efficacy of immune checkpoint inhibitors. To decipher this complexity, patient-derived organoid (PDO) models co-cultured with autologous immune cells have emerged as a validated platform that preserves tumor heterogeneity and enables real-time dissection of metabolism-immune circuits. This review systematically synthesizes current knowledge on the biological basis of MC plasticity, the metabolite-driven regulation of their function, and the utility of organoid-based systems for mechanistic discovery and drug screening. We critically evaluate emerging multidimensional therapeutic strategies, including pharmacological reprogramming of apMCs, metabolic normalization, and engineered cell therapies, and identify key knowledge gaps that must be addressed to translate these insights into clinical practice. By integrating advances in immuno-oncology, cancer metabolism, and bioengineering, this review provides a framework for translating current insights into clinically actionable strategies to overcome immunotherapy resistance in TNBC.