Compared with chimeric antigen receptor (CAR) T cell therapy, antibody-drug conjugates (ADCs) offer distinct advantages. Here, we report on two FGFR4-targeted ADCs, using the high-affinity monoclonal antibody 3A11, the same binder used in a CAR T cell format that is being evaluated at the NCI (NCT06865664) for patients with relapsed/refractory rhabdomyosarcoma (RMS). These ADCs, conjugated to monomethyl auristatin E (MMAE) or an exatecan derivative, are rapidly internalized, causing potent fibroblast growth factor receptor 4 (FGFR4)-dependent cytotoxicity in vitro. In subcutaneous RMS xenograft models, both ADCs demonstrated robust anti-tumor activities, significantly prolonging survival. Notably, exatecan-ADC showed better efficacy, with durable tumor control, in aggressive fusion-negative (FN) RMS559 and fusion-positive (FP) RH4 RMS cell-line-derived xenografts (CDXs) and a patient-derived RMS xenograft (PDX). Furthermore, exatecan-ADC effectively controls tumors in an FGFR4-expressing MDA-MB-453 breast cancer mouse model, eradicating relapsed tumors with retreatment. These findings highlight FGFR4-targeted ADCs as potent therapeutic agents against aggressive FGFR4-expressing malignancies, supporting their further clinical development.

Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8[+] T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic aminotransferase genes, which degrade tryptophan to indoles. Administration of B. uniformis harboring TnaA mutant fails to inhibit melanoma growth. Notably, administration of indoles effectively induces ATI and inhibits melanoma development. Correspondingly, the levels of bacterially encoded tryptophan-degrading enzymes are higher in cohorts of patients with melanoma responding to immunotherapy. These findings identify indoles as tryptophan breakdown products capable of inducing ATI resulting in melanoma inhibition.

Despite the clinical efficacy of PD-1/PD-L1 blockade in solid tumors, resistance mediated by PD-L1 protein stabilization necessitates alternative strategies. Our study identifies ethoxzolamide (EZA), a carbonic anhydrase inhibitor, as a negative regulator of PD-L1. EZA binds to the Leu387 residue of the E3 ubiquitin ligase β-TrCP, triggering K48-linked polyubiquitination and proteasomal degradation of PD-L1. Functionally, EZA downregulates tumor cell PD-L1, restoring T cell-mediated cytotoxicity in vitro. In Lewis lung carcinoma and MC38 murine models, EZA reprograms the tumor immune microenvironment (reducing MDSC/Treg infiltration while bolstering cytotoxic response). EZA synergizes with anti-CTLA-4 therapy to overcome treatment resistance. Clinical analysis of a neoadjuvant immunotherapy cohort of non-small cell lung cancer (NSCLC) patients reveals that high PD-L1 with low β-TrCP expression associates with superior response, suggesting that this axis may warrant further investigation. Our findings elucidate an antitumor mechanism of EZA and expand its therapeutic potential.

Oral cancer and cardiovascular disease share common modifiable risk factors and contribute substantially to the global burden of non-communicable diseases. However, evidence on their sex-specific coexisting burden at the population level remains limited, particularly in middle-income countries such as Malaysia. We conducted a national level, population-based analysis of the coexisting burden of oral cancer and cardiovascular disease in Malaysia using estimates from the Global Burden of Disease 2023 study. Age-standardized incidence rates, mortality rates, and disability-adjusted life year (DALY) rates from 1990 to 2023 were examined by sex. Joinpoint regression was applied to quantify temporal trends, and uncertainty intervals were propagated for all sex ratios. Risk-attributable fractions for tobacco and alcohol use were extracted from Global Burden of Disease's comparative risk assessment framework, and a combined metric of shared risk-attributable DALY burden was calculated. Population-level smoking prevalence data were obtained from the World Health Organization. In 2023, pronounced sex differences were observed for both conditions. Males exhibited higher age-standardized DALY and mortality rates than females, with male-to-female ratios of 1.68 (95% uncertainty intervals [UIs]: 1.31-2.10) for cardiovascular disease and 1.32 (95% UI: 1.08-1.61) for oral cancer age-standardized DALY rates. Despite comparable oral cancer incidence between sexes (M:F ratio = 0.97, 95% UI: 0.66-1.26), males had a 19% higher mortality-to-incidence ratio proxy (59.7% vs 50.2%). Tobacco use was the dominant driver of sex disparities, accounting for 37.9% of oral cancer DALYs and 25.8% of cardiovascular DALYs in males, compared with 7.8% and 8.7% in females. Joinpoint analysis revealed a recent upturn in male cardiovascular mortality (2019-2023) and a sharp rebound in oral cancer DALYs after 2018 in both sexes. This study quantifies a substantial sex-specific risk-attributable coexisting burden of oral cancer and cardiovascular disease in Malaysia, with males experiencing consistently higher mortality and DALY burden. Quantifying the shared risk contribution, males bore a 5-fold higher combined tobacco- and alcohol-attributable DALY burden than females (1702 vs 342 per 100,000), driven predominantly by tobacco use. The findings underscore the importance of integrated, sex-sensitive prevention strategies addressing shared risk factors and provide population-level evidence to inform public health policy in Malaysia and similar middle-income settings.

Chemotherapy-induced nausea and vomiting remains a frequent complication of cytotoxic therapy and can compromise treatment tolerance and adherence. This retrospective propensity score-matched cohort study evaluated the comparative effectiveness and safety of ondansetron-based dual versus triple antiemetic regimens in patients receiving chemotherapy for malignant tumors. Consecutive patients treated between January 2022 and July 2023 who underwent at least 2 chemotherapy cycles were identified from hospital records. Patients received either a dual regimen (ondansetron plus dexamethasone or aprepitant) or a triple regimen (ondansetron plus dexamethasone plus aprepitant). Propensity score matching (1:1) was conducted using sex, age, tumor type, metastatic status, Karnofsky performance status score, and history of motion sickness to reduce confounding, yielding 319 matched pairs. Across the first 2 chemotherapy cycles, the triple regimen achieved higher control rates for nausea and vomiting than the dual regimen, with statistically significant differences in overall efficacy in both cycles. Subgroup analyses suggested the greatest benefit of triple therapy among patients receiving highly emetogenic chemotherapy, whereas both strategies achieved high efficacy in moderately emetogenic settings. Adverse reactions were more frequent with the triple regimen in the first cycle, while between-group differences were attenuated in the second cycle. These findings support a risk-adapted approach that prioritizes triple therapy for highly emetogenic regimens with attention to tolerability.