Triple-negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis, early metastasis, resistance to treatments, and relapse. Despite progress in chemotherapy, surgery, and radiation, treatment outcomes remain limited, highlighting the urgent need for improved and safer therapeutic options or combination strategies. Monoclonal antibodies and other targeted therapies offer limited anti-tumor potency against heterogenous cancer cell populations, like those found in TNBC. Recent studies indicate that parasite-derived molecules hold promise as innovative anti-tumor agents; however, the molecular pathways driving their activity remain largely undefined, especially within heterogeneous cancer cell populations. Previous studies showed that Trypanosoma cruzi biomolecules can combat many types of cancer, including breast cancer, however, the molecular mechanisms behind T. cruzi extract-induced TNBC cell death remain to be elucidated. Recently published studies defined a role for Interleukin-6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling during early infection of primary human cardiac fibroblasts with T. cruzi trypomastigotes. In this study, we aim to understand the signaling mechanisms modulated in phenotypically distinct TNBC cells, MDA-MB-468 (epithelial-like) and BT-549 (mesenchymal-like), after treatment with cytotoxic T. cruzi cytosolic and membrane extracts. We treated TNBC cells, MDA-MB-468 and BT-549, with T. cruzi cytosolic and membrane extracts. Cell pellet was used to purify RNA for sequencing, preparation of cell lysate for immunoblotting assays and the conditioned media was used for ELISA assays. We evaluated the protein levels of IL-6, pSTAT3, and Suppressor of Cytokine Signaling 3 (SOCS3) in cell lysates and IL-6 secretion in condition media. RNA-sequencing showed significant upregulation of IL-6 transcripts in TNBC cells following treatment with parasite extracts. We observed upregulation of protein expression of IL-6 signaling molecules. This data corroborates recent studies suggesting that STAT3 signaling plays a role in T. cruzi pathogenesis. These findings highlight IL-6/STAT3 signaling as a potential mediator of parasite extract-induced TNBC cell death, offering new mechanistic insight into parasite-derived molecules as candidate anti-cancer therapeutics or additives. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Gonzalez et al. (Fri,) studied this question.