<p>The role of the immune response in influencing the therapeutic efficacy of systemic therapy for HER2-positive advanced breast cancer remains inadequately defined. This study included 82 patients with HER2-positive advanced breast cancer treated at Chenzhou No.1 People’s Hospital from March 2021 to March 2023 as the observation group, alongside 44 age-matched healthy female controls. The observation group received a TCbHP systemic therapy regimen. Peripheral blood T lymphocyte subsets (CD3⁺, CD4⁺, CD8⁺, and CD4⁺/CD8⁺ ratio) were measured before and after therapy. Serum levels of cancer antigen 15 − 3 (CA15-3), tissue polypeptide-specific antigen (TPS), and carcinoembryonic antigen (CEA) were also assessed. Prior to treatment, patients exhibited significantly lower CD3⁺, CD4⁺, and CD4⁺/CD8 ⁺ levels, and higher CD8 ⁺ levels compared to controls (<i>P</i> &lt; 0.05). Post-treatment, CD3⁺, CD4⁺, and CD4⁺/CD8⁺ levels significantly improved in patients with effective responses, particularly among those aged ≤ 60 years and with stage III disease (<i>P</i> &lt; 0.05). In contrast, patients with ineffective responses showed decreased CD3⁺ and CD4⁺/CD8 ⁺ levels and increased CD8 ⁺levels (<i>P</i> &lt; 0.05). Significant reductions in CA15-3, TPS, and CEA levels were observed post-treatment in the effective group (<i>P</i> &lt; 0.05). These findings suggest that systemic therapy enhances immune function and reduces tumor marker levels in this patient population, with more pronounced benefits in younger patients and those with earlier-stage disease. T lymphocyte subset changes may serve as valuable indicators of clinical response.</p>