Overcoming chemoresistance in triple-negative breast cancer (TNBC): Targeting PD-L1 stability and ferroptosis through integrated lipid metabolism and immune modulation.

Abstract

e15149 Background: Triple-negative breast cancer (TNBC) is notorious for its aggressive nature and high recurrence rates, exacerbated by the lack of specific molecular targets, leading to poor prognosis and emergent chemoresistance. Our study explores ferroptosis mechanisms in TNBC, focusing on the interaction between lipid metabolism and immune system modulation to identify targets that enhance chemosensitivity, potentially improving chemotherapy efficacy. Methods: We employed RNA transcriptomics, proteomics, metabolomics, and lipidomics to compare gene transcription, protein expression, and metabolic profiles between TNBC cell lines MDA-MB-231/ADR (doxorubicin-resistant) and MDA-MB-231/S (sensitive). The impact of the ferroptosis inducer Erastin on MDA-MB-231/ADR was assessed through lipidomics. We also performed gene expression profiling on 152 TNBC patients unresponsive to Anthracycline-based chemotherapy, correlating with data from TCGA and METABRIC. Functional loss and gain experiments were undertaken to explicate the role of the SCD1-TRIM28-PD-L1 axis in mediating ADR resistance. Immunohistochemistry and RT-qPCR analyses were performed on tumor tissues and serum EVs from TNBC patients to identify chemosensitivity-enhancing targets. Results: Our investigation revealed marked transcriptional and proteomic variances between MDA-MB-231/ADR and MDA-MB-231/S cell lines, with SCD1 showing significant upregulation at both mRNA and protein levels. Metabolomic analyses revealed distinct lipid metabolic profiles between these two cell lines. Further studies found that Erastin treatment increased PD-L1 expression, along with changes in SCD1, p53, and TNFAIP3 expression levels. These molecules are closely associated with poor prognosis and resistance to therapy. Our findings also elucidated that TRIM28 modulates PD-L1 stability via SUMOylation and facilitates p53 ubiquitination and degradation through a TRIM28-MDM2 dependent pathway, thereby impacting immune surveillance and therapeutic response. Additionally, in TNBC patients treated with anthracycline-based chemotherapy, higher SCD1 and TNFAIP3 but lower TRIM28 expressions were observed in the PD/SD group compared to PR/CR. Similar expression patterns were observed in serum EVs. Conclusions: Our study highlights the potential of targeting the SCD1-TRIM28-PD-L1 axis in TNBC to overcome chemoresistance. We propose combining SCD1 inhibition with ferroptosis inducers to enhance PD-L1 blockade efficacy, offering a promising approach for TNBC patients with limited response to Anthracycline-based chemotherapy. This investigation represents a pivotal step towards advancing targeted therapeutics in TNBC, potentially transforming the clinical management of this aggressive and refractory breast cancer subtype.