Background: In PD-L1+ mTNBC patients (pts), the standard of care treatment is chemotherapy and pembrolizumab (P) in the first-line setting. It has been shown that acquired resistance to P occurs as a result of immune exhaustion. Further, our group and others have demonstrated that chronic β2-adrenergic receptor (β-AR) signaling suppresses CD8⁺ cytotoxic T lymphocytes (CTL) function, drives their exhaustion, and increases the numbers of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumor microenvironment (TME), thus supporting tumor proliferation. Consequently, abrogation of β-AR signaling using the pan β-blocker propranolol or β-AR^-/^- knockout mice increased the intratumoral frequency of CTLs and elevated the CTL:Treg ratio (Bucsek et al. Cancer Res. 2017; PMID: 28819022). Similarly, mouse tumor models also demonstrated decreased exhaustion markers (PD1, TIM3, LAG3) on CTLs when β-AR was blocked, via propranolol (Qiao G et al. Cancer Immunol Res. 2021, PMID: 33762351). Confirming this phenomenon, we have shown, in a prospective clinical trial in metastatic melanoma, that β-AR blockade with propranolol significantly increased response to P with an objective response rate (ORR) of 78%, as opposed to 30-40% with P monotherapy (Gandhi et al, Clin Cancer Res 2021, PMID: 33127652). Therefore, we hypothesize that using propranolol in an ICI refractory population should improve responses to ICIs. Methods: This is a phase II single-arm, non-randomized single-center study for mTNBC pts. Participants will bewomen >=18 yrs with PD-L1+ mTNBC, who have progressed on treatment with chemotherapy and P in the upfront setting. They will continue P every 3 weeks in addition to 30 mg propranolol twice a day, based on our ongoing clinical trial in metastatic melanoma (NCT03384836) which has demonstrated safety with this combination. Treatment will continue until disease progression per irRECIST. The primary endpoint is ORR, defined as complete or partial response to treatment. The secondary endpoint is safety, 6-month progression-free survival and overall survival. As an exploratory endpoint, changes in tumor and blood immune markers will be assessed. In stage 1, n1=12 evaluable pts will be enrolled. If ≥ 1/12 response is observed, then the study will continue to enroll another n2=9 pts for a total of n=21, otherwise it will be suspended for futility. If ≥ 3/21 responses are observed, then the proposed therapy will be considered promising. Pre- and post-treatment tumor biopsies and sequential blood samples will be analyzed for changes in stress-induced biomarkers (epinephrine, norepinephrine, and frequency of CTL, MDSC, Treg) and expression of exhaustion markers (PD1, TIM3, LAG3). The study is currently open. Clinical trial information: NCT05741164.