Yi Huang

Background: CD47 functions as a “don’t eat me” checkpoint, inhibiting macrophage-mediated phagocytosis in triple-negative breast cancer (TNBC). While anti-CD47 therapies can restore immune surveillance, their efficacy in TNBC is often limited by immune evasion and drug development challenges. Methods: We investigated the crosstalk between the histone demethylase lysine-specific demethylase 1 (LSD1) and CD47 signaling in TNBC using in silico datasets, isogenic cell lines, conditional BRCA1 knockout models, and syngeneic mouse models. Techniques such as immunohistochemistry, multiplex immunofluorescence, immunoprecipitation, protein ubiquitination, chromatin immunoprecipitation, chemotaxis, flow cytometry, and phagocytosis assays were employed to examine the epigenetic regulation of CD47 by LSD1 and its impact on antitumor immunity. The efficacy of combining LSD1 inhibition with anti-CD47 therapy was evaluated in BALB/cJ mice bearing TNBC tumors. Results: In TNBC tumors, CD47 expression is positively correlated with elevated LSD1 levels, which are associated with increased infiltration of M2 macrophages and a concomitant decrease in M1 macrophages and CD8+T cells. Inhibition of LSD1 led to downregulation of CD47 by suppressing the expression and activity of its key transcriptional regulators, NF-κB (p65) and STAT3, through distinct mechanisms. Loss of LSD1 reduced p65 transcription, which was linked to an accumulation of the repressive histone mark H3K9me2 at the p65 promoter. Conversely, LSD1 inhibition promoted polyubiquitination and subsequent destabilization of STAT3. LSD1 inhibition also enhanced phagocytosis and promoted M1 polarization of macrophages. CD47 downregulation induced the production of interferon-γ and Th1-type chemokines in TNBC cells, facilitating increased tumor infiltration of CD8+T cells. Furthermore, combining LSD1 inhibition with anti-CD47 therapy significantly improved antitumor efficacy compared with monotherapy in syngeneic tumor models, without inducing significant toxicity. This combination therapy also promoted a shift in macrophage polarization toward the M1 phenotype, further enhancing CD8+T cell infiltration within tumors. Depletion of CD8+T cells significantly diminished the antitumor efficacy of the combination therapy. Conclusion: Targeting LSD1 enhances the efficacy of anti-CD47 therapy by overcoming immune evasion, offering a promising strategy to improve immunotherapy outcomes in TNBC.

FABP5 mediates lipid incorporation

Obesity is strongly associated with triple-negative breast cancer (TNBC). A better understanding of the molecular mechanisms driving obesity-induced TNBC progression could facilitate the development of precision dietary intervention strategies. In this study, we used murine models of obesity induced by different high-fat diets (HFD) to examine their impact on TNBC progression. Compared with a low-fat diet, both cocoa butter and olive oil HFDs induced similar levels of obesity. However, only the olive oil HFD–induced obesity increased TNBC stemness and lung metastasis. Mechanistically, oleic acid (OA) in the olive oil HFD facilitated TNBC metastasis by activating the protein kinase C (PKC)–aldehyde dehydrogenase (ALDH) pathway. Furthermore, fatty acid–binding protein 5 (FABP5) in TNBC cells was identified as essential for OA-mediated PKC–ALDH pathway activation. FABP5 deficiency reduced TNBC metastasis in multiple mouse models, whereas higher FABP5 expression correlated with worse outcomes of TNBC in various human studies. These findings collectively suggest that the consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling.Significance:Comparison of obesity induced by different high-fat diets revealed that an olive oil-based diet promotes triple-negative breast cancer metastasis by activating FABP5/PKC/ALDH signaling, providing a target for the development of obesity-associated cancer therapeutics.

HFD-associated immunophenotypes

OA-induced tumor invasion in vitro