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

Abstract

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.