Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic targets. Hypoxia, autophagy, apoptosis, and translational stress are key biological processes involved in tumor progression and treatment resistance, but their predictive value for neoadjuvant chemotherapy (NACT) response remains unclear. This study aimed to investigate the association of hypoxia-related (HIF-1α), autophagy-related (Beclin-1, LC3A), apoptosis-related (Bcl-2), and translational stress–related (eIF2α) markers with response to NACT in TNBC, and to explore their relationships with clinicopathological features and survival outcomes.

Fifty-seven patients with TNBC who received NACT were retrospectively analyzed. Pretreatment tru-cut biopsy specimens were immunohistochemically stained for HIF-1α, Beclin-1, LC3A, Bcl-2, and eIF2α. Marker expression was evaluated using two semi-quantitative scoring systems. Pathological response was assessed using the Miller–Payne (MP) system and Residual Cancer Burden (RCB) classification. Associations with clinicopathological parameters, Miller–Payne (MP) and Residual Cancer Burden (RCB) systems, post-NACT morphological features, and survival were assessed using Spearman correlation, Kruskal–Wallis test, ROC analysis, chi-square tests, and Kaplan–Meier survival.

Beclin-1 expression was significantly associated with higher MP response (p = 0.019) and demonstrated meaningful discriminatory ability for predicting good response (p = 0.02). HIF-1α showed a weak positive correlation with MP score (p = 0.042) and a borderline predictive trend (p ≈ 0.078). LC3A, Bcl-2, and eIF2α did not show significant predictive value for treatment response. Stromal HIF-1α expression was significantly associated with increased stromal lymphocytic infiltration (p = 0.009), reduced residual invasive tumor following NACT (p = 0.039), and increased foamy/hemosiderin-laden macrophages (p = 0.020–0.039), indicating hypoxia-related stromal remodeling. None of the biomarkers predicted overall or disease-free survival, whereas high MP response and RCB 0–1 were strong predictors of favorable outcomes.

Beclin-1 and stromal HIF-1α may serve as useful predictors of pathological response to NACT in TNBC, reflecting the biological impact of autophagy activation and hypoxia-mediated stromal modulation. Incorporation of these markers into pretreatment evaluation may improve response stratification in TNBC.