Tumor immunosenescence drives breast cancer progression and therapeutic resistance: mechanisms and emerging interventions.

Breast cancer remains the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. While immune checkpoint inhibitors have transformed treatment for a subset of patients, durable responses remain limited, in part because the tumor immune microenvironment is profoundly shaped by age-associated immune decline-termed immunosenescence. In this review, we critically synthesize how tumor immunosenescence may contribute to breast cancer progression and therapeutic resistance, distinguishing correlative observations from mechanistically established relationships. We examine T cell senescence and exhaustion as mechanistically separable states with distinct therapeutic implications, and evaluate the roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) as orchestrators of immunosenescence through SASP production, immune exclusion, and metabolic remodeling. We discuss subtype-specific immunosenescence signatures (TNBC, HER2+, HR+), hormonal and menopausal influences, stage-dependent immune alterations, and BRCA-associated susceptibility. The senescence-associated secretory phenotype (SASP)-comprising IL-6, IL-8, TGF-β, and matrix metalloproteinases-serves as a central mediator linking cellular senescence to immune evasion and metastatic dissemination, though much of the evidence derives from preclinical models. Therapy-induced senescence following chemotherapy and radiotherapy may paradoxically drive relapse through SASP-mediated immunomodulation, a hypothesis that lacks prospective clinical validation. We review clinical evidence that aging is associated with diminished interferon signaling, reduced tumor-infiltrating lymphocyte density, and altered checkpoint blockade efficacy in some but not all studies, acknowledging substantial inter-patient heterogeneity. We highlight recent advances in single-cell and spatial profiling technologies and discuss challenges in biomarker standardization and clinical implementation. Finally, we evaluate emerging interventions-senolytics (navitoclax, dasatinib plus quercetin, fisetin), senomorphics, metabolic rescue via NAD+ repletion, STING agonists, and rational senotherapy-immunotherapy combinations-emphasizing that most remain at preclinical or early clinical stages. We conclude that targeting tumor immunosenescence represents a promising but incompletely validated therapeutic axis for enhancing anti-tumor immunity in breast cancer.