Understanding the factors that influence therapeutic response and prognosis is crucial for improving the management of HER2-positive breast cancer (HER2+BC). Despite the success of neoadjuvant therapy (NAT), predicting pathological response and long-term outcomes remains a major challenge. Tumor-infiltrating lymphocytes (TILs) have emerged as immune biomarkers associated with response to NAT and prognosis. At the same time, redox biology plays a fundamental role in shaping the cancer cell phenotype and the tumor microenvironment. However, the extent of their impact on HER2+BC progression and treatment outcomes is still unclear. This study aims to investigate the interplay between immune infiltrates and oxidative stress in HER2+BC, integrating bioinformatics to identify redox-related genes linked to prognosis and immune modulation.

Surgically resected specimens from 30 patients with early HER2+ BC who underwent neoadjuvant chemotherapy with trastuzumab and pertuzumab were analysed for TILs (hematoxylin-eosin) and the oxidative damage biomarker 3-nitrotyrosine (3-NT, immunohistochemistry). To explore the associations between the expression of redox-related genes with tumor microenvironment cell populations and patient survival, a bioinformatics study using the TCGA dataset and the GEPIA and TIMER2.0 platforms was performed.

TILs score correlated positively with tumor size, both at diagnosis and after NAT. 3-NT scores correlated with tumor size at diagnosis and TILs score. Based on the associations identified between TILs, clinical features and oxidative damage, a bioinformatics analysis was conducted to explore redox-related genes that could be critical for HER2+BC prognosis. We identified 53 redox-related genes for which dysregulated expression is associated with survival, with 43 genes associated with higher hazard ratios (HR) and 10 with lower HR. Some of these genes are associated with a higher abundance of specific immune cell populations infiltration. Genes are mostly related to oxidative phosphorylation, response to oxidative stress, and regulation of transcription. Four main pathways are shared by some of the genes identified: HMOX1, TP53-mediated translational control, regulation of PTEN transcription, and VEGFA-VEGFR2 signalling.

This study provides novel insights into the interplay between redox biology and tumor immunity in HER2+BC. The identification of redox-related genes associated with survival and immune modulation suggests potential prognostic biomarkers. Further research should validate these findings, paving the way for more precise and personalized therapies. Acknowledgements: Fundação para a Ciência e a Tecnologia (FCT) through projects DOI 10.54499/UIDP/04567/2020 and DOI 10.54499/UIDB/04567/2020 to CBIOS. B.Inov Grant from SRSRA-OF 2024.