CDK4/6 inhibitors as conditional immune-priming agents in breast cancer: therapeutic windows, sequencing strategies, and rational combinations with immunotherapy, radiotherapy, and antibody-drug conjugates.

UNLABELLED: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are established components of endocrine therapy for hormone receptor-positive (HR+), HER2-negative breast cancer. Beyond RB-dependent G1 arrest, these drugs alter antigen presentation, interferon signaling, checkpoint-ligand expression, suppressive immune-cell populations, and CD8+ T-cell fate. The direction and durability of these effects vary across tumors and treatment settings. Early combinations with immune checkpoint inhibitors (ICIs) have produced activity signals, but hepatotoxicity and pneumonitis have limited several regimens. Radiotherapy and antibody-drug conjugates (ADCs) offer different routes to antigen release and innate immune activation. Therapeutic vaccination and dendritic-cell support provide a further route to exploit treatment-induced antigen display, although this rationale remains preclinical. We examine CDK4/6 inhibitors as conditional immune-priming agents whose value depends on baseline immune contexture, tumor-cell-cycle dependence, endocrine therapy, drug and dose, exposure duration, partner treatment, and organ reserve. Here, immune priming is an operational term for a treatment-induced immune state that a subsequent therapy may use; it does not imply proven de novo activation of naïve T cells. Evidence is separated into clinical outcomes, human translational findings, preclinical mechanisms, and testable hypotheses. This synthesis supports a therapeutic-window strategy in which a defined exposure is assessed for a measurable immune change before treatment is escalated. The immediate translational challenge is to identify that window, determine when it can be exploited, and recognize when continued exposure is more likely to reinforce resistance or toxicity. SYSTEMATIC REVIEW REGISTRATION: https://clinicaltrials.gov/study/,identifier NCT05766410.