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Hepatocellular carcinoma (HCC) is the most prevalent primary malignancy of the liver. Characterized by rapid progression and poor overall survival rates, HCC requires effective and streamlined treatment regimens. It predominantly occurs in East Asia and sub-Saharan Africa, where it has historically been managed with herbal formulas. We previously observed that the herbal formula HO-1089 exerts potent anti-HCC effects both in vitro and in vivo. In this study, we investigated the anticancer efficacy and mechanisms of HO-1197, a reconstituted herbal formulation derived from HO-1089. HO-1197 selectively inhibited the viability of HCC cell lines without hepatotoxicity and demonstrated superior anticancer activity compared with both HO-1089 and sorafenib. Mechanistically, HO-1197 induced apoptosis and G2/M arrest through reactive oxygen species-mediated DNA damage, independent of p53 status. Transcriptomic analysis revealed downregulation of mitosis-related genes, particularly those regulated by FOXM1, a key driver of HCC proliferation and metastasis. HO-1197 suppressed FOXM1 expression and nuclear translocation, reducing its downstream targets and diminishing angiogenic and metastatic potential. Furthermore, HO-1197 modulated the tumor immune microenvironment by promoting pro-inflammatory macrophage polarization and enhancing natural killer cell-mediated cytotoxicity. HO-1197 exhibited potent antitumor efficacy, and combination therapy with HO-1197 and sorafenib exhibited synergistic effects in both two-dimensional and immune-activated multicellular spheroid models. These findings suggest that HO-1197 is a promising multifunctional therapeutic candidate with antitumor, antiangiogenic, antimetastatic, and immunomodulatory properties. Its combination with sorafenib may offer effective treatment for HCC. HO-1197, which demonstrated strong efficacy, is a novel herbal medicine developed by H&O Biosis and is referred to as an Integrated Natural Medicine.

Assessment of Fc receptors and immune cells in breast cancer enables development of tailored engineering strategies for tumor-targeting monoclonal antibodies with enhanced immune-stimulating and anticancer attributes by combining glycoengineering and Fc mutations. AbstractFc engineering to enhance antibody effector functions harbors the potential to improve therapeutic effects. Understanding Fc¦ÃR expression and distribution in the tumor microenvironment prior to and following treatment may help guide immune-engaging antibody design and patient stratification. In this study, we investigated FcR-expressing immune effector cells in HER2+ and triple-negative breast cancers (TNBC), including neoadjuvant chemotherapy¨Cresistant disease. Fc¦ÃRIIIa expression, Fc¦ÃRIIIa+ NK cells, and classically activated (M1-like) macrophages correlated with improved anti-HER2 antibody efficacy. Fc¦ÃRIIIa protein and Fc¦ÃRIIIa+ NK cells and macrophages were present in primary TNBC and retained in treatment-resistant tumors. Fc¦ÃRIIIa was spatially associated with folate receptor alpha¨Cpositive (FR¦Á+) tumor areas at baseline and in residual tumors following neoadjuvant chemotherapy. Wild-type and Fc-engineered antibodies recognizing two breast cancer¨Cassociated antigens, HER2 and the emerging TNBC target FR¦Á, were designed and generated to have increased Fc¦ÃRIIIa-expressing effector cell engagement. The combination of glycoengineering, including fucose removal from the N-linked Fc glycan, and Fc point mutations greatly increased antibody affinity for and retention on Fc¦ÃRIIIa. The Fc-engineered antibodies enhanced immune effector activity against HER2+ breast cancer and TNBC, altering proinflammatory cytokine production by NK cells and tumor-conditioned macrophages and skewing macrophages toward proinflammatory states. Furthermore, the Fc-engineered antibodies restricted orthotopic HER2+ and FR¦Á+ breast cancer xenograft growth at doses suboptimal for equivalent wild-type antibodies and recruited Fc¦ÃRIIIa-expressing cells into tumors. Antibody design through combined glycoengineering and Fc point mutations to enhance Fc¦ÃRIIIa engagement of tumor-infiltrating effector cells may be a promising strategy for developing therapies for patients with aggressive and treatment-resistant breast cancers.Significance:Assessment of Fc receptors and immune cells in breast cancer enables development of tailored engineering strategies for tumor-targeting monoclonal antibodies with enhanced immune-stimulating and anticancer attributes by combining glycoengineering and Fc mutations.

Atovaquone, an FDA-approved oxidative phosphorylation (OXPHOS) inhibitor, has shown promise in the treatment of epithelial ovarian cancer (EOC), the deadliest gynecologic malignancy. However, the precise mechanisms underlying its antitumorigenic effects remain unclear. We employed a longitudinal transcriptomic approach to characterize the molecular effects of atovaquone on EOC cells. Our findings demonstrate that atovaquone disrupts cellular homeostasis and metabolism, activates stress responses, and primes immune recognition. We observed temporal downregulation of genes and pathways involved in key cellular processes, such as the cell cycle and DNA replication, which correlated with reduced proliferative capacity. Atovaquone also downregulated both OXPHOS and glycolysis while upregulating the pentose phosphate pathway, suggesting a metabolic shift toward redox homeostasis restoration in response to severe oxidative stress. Consistent with oxidative stress, we found that atovaquone activated endoplasmic reticulum (ER) stress, which is linked to immunogenic cell death. During ER stress, calreticulin, a damage-associated molecular pattern (DAMP), translocates to the plasma membrane, where it promotes immune recognition. We observed that calreticulin was upregulated on the plasma membrane of atovaquone-treated EOC cells. Additionally, we detected increased levels of other DAMPs, such as high mobility group box 1 (HMGB1) and mitochondrial transcription factor A (TFAM), in the supernatants of atovaquone-treated cells, indicating the release of immunogenic molecules. Moreover, increased expression of ligands for activating receptors of NK cells was observed, and coculture experiments revealed enhanced NK cell activity toward atovaquone-treated cells. These results highlight atovaquone¡¯s potential to activate immune responses, offering a new avenue for combination therapies in EOC treatment.