Highlighted Research Articles

Medicaid expansion is associated with improvements in insurance coverage, early detection and treatment services, and 2-year overall survival. However, whether this translates to improvements in longer-term survival remains unknown. Schafer and colleagues found Medicaid expansion led to a greater increase in 5-year overall and cause-specific survival among individuals diagnosed with cancer residing in rural and high poverty areas and among cancers that typically have worse prognosis. These findings underscore the importance of expanding Medicaid in the 10 remaining non-expansion states and protecting expansion in the states that have already implemented it, in order to improve outcomes for all individuals.See article, p. 2431.Metastatic breast cancer cells undergo extensive metabolic rewiring to colonize distant organs. Through mitochondrial metabolomics, Yeh, DelGaudio, and colleagues identified mitochondrial glutathione (GSH) accumulation during lung metastasis, driven by upregulation of the GSH transporter SLC25A39. Loss of SLC25A39 impaired metastatic colonization across genetic models and patient-derived xenografts without affecting primary tumor growth. They found mitochondrial GSH import to be essential during early colonization and acting independently of antioxidant defense. Mechanistically, SLC25A39 promotes ATF4 activation under hypoxia, linking mitochondrial GSH availability to the integrated stress response. These findings establish mitochondrial GSH import as a key metabolic requirement for metastatic progression.See article, p. 2437.Anti−PD-1 immunotherapy has demonstrated significant anti-tumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), but resistance remains a substantial challenge. Huang, Gao, Chen, and colleagues showed that combining DNMT inhibitors with anti−PD-1 exhibits superior efficacy with tolerable safety in patients with R/R NKTL who have failed prior anti−PD-1 therapy. Mechanistically, DNMT inhibitors induced viral mimicry response, activated interferon signaling, and remodeled the tumor microenvironment, thereby overcoming resistance to anti−PD-1 therapy in preclinical models. These findings provide both strong clinical evidence and mechanistic insights for this novel epigenetic-immunotherapeutic strategy in NKTL.See article, p. 2450.Verma, Zeig-Owens, Goldfarb, and colleagues uncover how exposure to the toxic dust released during the 9/11 World Trade Center disaster has shaped the long-term blood health of first responders. Through genomic analysis of nearly 1,000 responders and two control cohorts, they revealed a significantly higher burden of clonal hematopoiesis among exposed individuals, including distinct spectrum of mutations in younger responders. Those with clonal mutations faced a substantially increased risk of developing leukemia. In experimental models, particulate exposure triggered inflammation and accelerated the growth of mutant blood cells. The study identifies IL1RAP as a key driver of this expansion and a potential therapeutic target.See article, p. 2468.Patients with kidney cancer who develop hypercalcemia (HC) face poor outcomes, yet the molecular basis of HC is unclear. This study shows that HIF-2 induces PTHLH (PTHrP) expression leading to HC in aggressive, frequently sarcomatoid/rhabdoid, clear cell renal cell carcinoma (ccRCC). In studies of tumorgraft models and patients, Mal, Xie, and colleagues demonstrated that HIF-2 inhibitors (PT2399 and PT2977/belzutifan) suppress PTHLH expression without affecting chromatin accessibility and rapidly normalize calcium in ccRCC. These findings identify PTHrP and HC as potentially predictive therapeutic biomarkers and support evaluating HIF-2 antagonists for patients with ccRCC and paraneoplastic HC.See article, p. 2485.Cancer cell–based phenotypic screens can reveal unexpected small molecule activities. Yuan, Ji, Dwyer, and colleagues used phenotypic screens to redefine the clinical-stage compound PRLX-93936, previously of unknown mechanism, as a molecular glue that reprograms the E3 ligase TRIM21 to degrade nuclear pore complex proteins. Optimized analogs demonstrated enhanced potency and efficacy in pancreatic cancer models, and TRIM21 expression served as a predictive biomarker, highlighting the translational potential of TRIM21-mediated nuclear pore degradation. This study uncovers a mechanism of cancer cell vulnerability and illustrates the value of reexamining discontinued clinical agents to identify new therapeutic opportunities.See article, p. 2505.Small GTPase regulators are crucial in cancer but are numerous and redundant, hindering evaluation. Zhang, Cao, and colleagues utilized functional genetic screens of GAPs and GEFs, including paired perturbations, to uncover blood cancer–specific dependencies. They identify ARHGAP45, a minor histocompatibility antigen, as a shared vulnerability across blood malignancies yet dispensable in normal blood cells. ARHGAP45-expressing cells could be eliminated by engineered hybrid TCR-CAR T cells recognizing an ARHGAP45-derived antigen, and pharmacologic targeting of CDC42, which is required upon ARHGAP45 loss, enhanced these therapies. This study provides a framework for probing druggable GTPase regulators and highlights ARHGAP45 as a promising therapeutic target.See article, p. 2530.To elucidate functional epigenomic regulators that drive lung cancer, Tang and colleagues developed a barcoded CRISPR-Cas9 screening approach with clonal resolution. This high-throughput strategy identified multiple epigenomic tumor suppressor genes and tumor dependency genes. Notably, they discovered that a specific HBO1 complex and the MLL1 complex cooperated to restrain lung adenocarcinoma development across diverse genetic contexts. These findings provide a functional road map of epigenomic regulation in lung adenocarcinoma.See article, p. 2554.