Introduction: In recent years, PD-1 inhibitors and Trop2-ADC have been approved for the treatment of triple-negative breast cancer (TNBC). However, the efficacy of PD-1 inhibitor monotherapy is modest, benefiting only a small proportion of patients with TNBC. Chemotherapy remains the cornerstone of TNBC treatment; nevertheless, the risk of recurrence with these therapies remains high over time. Consequently, there is an urgent need to enhance the efficacy of immunotherapy and chemotherapy in patients with TNBC. TY-2699a, an orally active and highly selective CDK7 inhibitor developed by TYK Medicines, has shown monotherapy efficacy in TNBC (DCR 50%) and favorable tolerability, with lower gastrointestinal toxicity and manageable hematologic adverse events, supporting its potential for combination therapy in TNBC. Results: In this study, we discovered that TY-2699a enhanced the efficacy of Gemcitabine and Nab-paclitaxel in TNBC HCC70 CDX mouse models when combined with TY-2699a, respectively. We observed that TY-2699a effectively killed EMT6 cells in vitro and improved PD-1 efficacy both in vitro and in an EMT6 syngeneic CDX mouse model. These findings warrant further investigation to determine whether TY-2699a enhances PD-1 efficacy in a TNBC 4T1 mouse model. Previously, we reported that TY-2699a is more potent than FDA-approved CDK4/6 inhibitors in head and neck squamous cell carcinoma (HNSCC). T-DXd (DS-8201) treatment achieved an ORR of 58.8% and a PFS of 20.5 months in patients with HER2-expressing salivary gland carcinoma (SGC). Our data suggest that TY-2699a and T-DXd act a synergistically effect on HNSCC Cal33 cells. Cetuximab is the only FDA-approved targeted therapy agent for HNSCC. Interestingly, we found that TY-2699a significantly enhanced the efficacy of Cetuximab in HNSCC FaDu cells both in vitro and in a CDX mouse model. In summary, TY-2699a demonstrated antitumor efficacy as a monotherapy in TNBC, achieving a DCR of 50% with a manageable clinical safety profile. Beyond its role as a monotherapy, TY-2699a holds significant promise for use in combination therapies with chemotherapy or immunotherapy in TNBC and HNSCC. * Correspondence to: Shengli Dong and Apeng Liang.