Despite advances in early detection and targeted therapies, breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide. Resistance develops through the interplay of tumor-intrinsic heterogeneity and tumor-extrinsic influences, including the tumor microenvironment and immune–metabolic interactions. This complexity drives therapeutic evasion, metastatic progression, and poor outcomes. Resistance mechanisms include drug efflux, genetic mutations, and altered signaling pathways. Additional contributors are cancer stem cell plasticity, exosomal RNA transfer, stromal remodeling, epigenetic alterations, and metabolic reprogramming. Microbial influences and immune evasion further reduce treatment effectiveness. Collectively, these processes converge on regulated cell death (RCD) pathways—apoptosis, ferroptosis, and pyroptosis—where metabolic shifts and immune suppression recalibrate cell death thresholds. Nutrient competition, hypoxia-driven signaling, and lactate accumulation weaken antitumor immunity and reinforce resistance niches. In this review, we synthesize the genetic, metabolic, epigenetic, immunological, and microenvironmental drivers of BC resistance within a unified framework. We highlight the convergence of these mechanisms on RCD and immune–metabolic signaling as central principles. Artificial intelligence (AI) is emphasized as a cross-cutting connector that links major domains of resistance biology. AI supports early detection through ctDNA and imaging, predicts efflux- and mutation-driven resistance, models apoptotic and ferroptotic vulnerabilities, and stratifies high-risk patients such as TNBC patients.
尽管早期检测和靶向治疗已取得进展，乳腺癌仍是全球女性癌症相关死亡的主要原因。耐药性的产生源于肿瘤内在异质性与肿瘤外在影响的相互作用，包括肿瘤微环境及免疫-代谢交互作用。这种复杂性驱动了治疗逃逸、转移进展及不良预后。耐药机制包括药物外排、基因突变和信号通路改变。其他影响因素涵盖肿瘤干细胞可塑性、外泌体RNA转移、基质重塑、表观遗传改变及代谢重编程。微生物影响和免疫逃逸进一步降低了治疗效果。这些过程共同汇聚于调节性细胞死亡通路——凋亡、铁死亡和焦亡，其中代谢转变和免疫抑制重新校准了细胞死亡阈值。营养竞争、缺氧驱动信号传导和乳酸积累削弱了抗肿瘤免疫并强化了耐药生态位。本综述在统一框架下整合了乳腺癌耐药性的遗传、代谢、表观遗传、免疫及微环境驱动因素，重点阐释这些机制在调节性细胞死亡和免疫-代谢信号传导上的汇聚效应作为核心原理。人工智能被强调为贯穿耐药生物学主要领域的交叉连接器，其通过循环肿瘤DNA和影像学支持早期检测，预测外排及突变驱动的耐药性，模拟凋亡与铁死亡脆弱性，并对三阴性乳腺癌等高危患者进行风险分层。
The Underlying Mechanisms and Emerging Strategies to Overcome Resistance in Breast Cancer
肿瘤(癌症)患者之家