Differential peripheral immune dynamics underlie therapeutic response to chemotherapy and chemoimmunotherapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and response to immune checkpoint inhibitors. Tumor-infiltrating lymphocytes have been extensively studied; however, the integration of peripheral immune dynamics with mechanistic regulation underlying therapeutic response remain poorly defined. Here, we integrate immune-state modeling with pathway-level mechanistic inference to analyze single-cell RNA sequencing of PBMCs from patients with advanced TNBC treated with paclitaxel alone or in combination with the anti-PD-L1 Ab atezolizumab. This framework leverages treatment arm, longitudinal sampling, and clinical response to resolve coordinated immune programs across lymphoid and myeloid compartments. We identified distinct treatment- and response-specific states before and after treatment. Chemotherapy responders displayed pretreatment adaptive immune priming, whereas combination-therapy responders exhibited preexisting effector T-cell activity coupled with tumor PD-L1 expression. In contrast, chemotherapy nonresponders developed persistent post-treatment immune dysregulation in regulatory and terminal effector programs, whereas combination-therapy nonresponders demonstrated maladaptive remodeling of adaptive and innate compartments, including dysfunctional NK and metabolically reprogrammed myeloid populations. Across regimens, pathways involving protein translation, metabolic adaptation, and stress signaling emerged as shared modulators of response. These findings suggest that coordinated adaptive-innate immune dynamics underlie therapeutic efficacy, whereas systemic immune exhaustion and myeloid immunoregulation lead to resistance. Projection of these peripheral immune programs onto independent I-SPY2 showed concordant associations with tumor immune phenotypes and pathological complete response, supporting generalizability of the findings. Our study demonstrates the utility of an integrative approach for linking peripheral immune state organization with mechanistic insights, informing response in TNBC.