Cyclin-dependent kinase 4 and 6 inhibitors and the breast cancer immune ecosystem: immune remodeling, resistance, and therapeutic reprogramming.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) combined with endocrine therapy have become a therapeutic backbone for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, yet durable disease control is frequently limited by intrinsic and acquired resistance. Canonical tumor-cell mechanisms, including retinoblastoma-pathway escape, cyclin E-cyclin-dependent kinase 2 (CDK2) activation, endocrine adaptation, and phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling, explain only part of this failure because they do not fully capture dynamic immune and stromal remodeling. Preclinical and translational studies indicate that early CDK4/6 inhibition can enhance antigen presentation, activate interferon-related programs, restrain regulatory T cells, and promote a T-cell-inflamed state. These effects are conditional and may not persist during prolonged treatment. Sustained therapy can instead drive heterogeneous resistant niches characterized by stromal remodeling, myeloid recruitment, checkpoint adaptation, and T-cell dysfunction. This immune-state dependence provides a rationale for immune checkpoint blockade, although clinical combinations have shown mixed efficacy and clinically relevant hepatic, pulmonary, and hematologic toxicities. Sequential or lead-in strategies therefore warrant prospective evaluation. Oxidative phosphorylation (OXPHOS) and redox adaptation may sustain selected resistant states and expose context-dependent ferroptotic vulnerabilities. Ferroptosis may connect tumor-cell killing with immune regulation, whereas nanomedicine may improve tumor-selective delivery. Both strategies remain largely preclinical and require further evaluation of pharmacokinetics, biodistribution, toxicity, manufacturability, and immune-cell safety. This Review distinguishes intrinsic from acquired resistance across interpatient, intratumoral, spatial, and temporal dimensions. It integrates tumor-cell escape with cytokine, immune, stromal, vascular, and metabolic remodeling and summarizes emerging therapeutic strategies. We further propose a candidate biomarker-informed framework that integrates genomic profiling, spatial immune architecture, circulating biomarkers, T-cell receptor (TCR) dynamics, transcriptomic and single-cell analyses, artificial intelligence (AI)-assisted multimodal integration, and longitudinal sampling. This framework is intended to support biomarker development and prospective trial design rather than current clinical decision-making, providing a translational basis for testing state-informed and sequence-aware therapeutic strategies.