Highlighted Research Articles

Xu, Deng, Liu, Zhuo, Zhu, Chang, Liu, Fu, Li, Liu, and colleagues launched a multicenter, prospective, single-arm, phase II clinical trial and included 34 patients with PD-L1+, persistent, recurrent or metastatic cervical cancer to receive first-line de-escalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab. They reached an objective response rate of 93.8%. Multiomic analysis demonstrated that heightened chemotaxis and proliferative activity of tumor-infiltrating T cells and activated germinal center B cells informed optimal treatment response. Higher TLS-to–tumor area ratio was correlated with improved survival. These findings lay the foundation for the feasibility of first-line de-escalated chemotherapy plus immune-targeted therapies for the clinical management of patients with metastatic, persistent, or recurrent cervical cancer.See article, p. 439.An understanding of tumor cell dynamics can inform prognosis and treatment decisions but remains limited in lung adenocarcinoma in never smokers (NS-LUAD). Using RNA sequencing from 684 NS-LUAD tumors with independent validation, Zhao and colleagues identified three robust molecular subtypes with distinct cellular programs, genomic features, and survival outcomes. These subtypes differed in proliferation, differentiation, and tumor cell states and composition, resulting in marked prognostic differences, even among stage I tumors. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or established genomic features, highlighting its potential clinical utility in early-stage NS-LUAD.See article, p. 460.Patients with end-stage renal disease (ESRD) develop acquired cystic kidney disease (ACKD) and renal tumors, yet the causal biology is unclear. To investigate this, Takahashi, Tanaka, and colleagues performed integrated spatial immunogenomic analysis of 268 specimens, revealing that ESRD-associated tumors are molecularly distinct from sporadic renal cell carcinoma. ACKD exhibited an inflammatory microenvironment, and renal cysts developed from proximal tubular cells that survived inflammation and expanded clonally, while microenvironmental signals drove paracrine MET activation to support tumorigenesis. These data define pathogenic circuits in ESRD and suggest preventative strategies.See article, p. 478.Huang, Hagihara, and colleagues profiled 1,582 intestinal metaplasias (IM) across six countries with varying gastric cancer incidence, identifying recurrent driver mutations, IM-specific mutational signatures, and Helicobacter pylori variants associated with regional gastric cancer risk. Matched blood analyses demonstrated that clonal hematopoiesis (CH), associated with age and smoking, was independently associated with progression to dysplasia and gastric cancer. CH carriers showed greater abundance of oral bacteria within IM regions, suggesting disruptions in host mucosal immunity. These findings pave the way for molecularly stratifying patients with IM by their future gastric cancer risk and point to potential targeted prevention strategies for IM.See article, p. 497.Loss of the tumor suppressor PTEN is a frequent driver of aggressive, treatment-resistant cancers, yet targeted therapies remain elusive. Tang, Zhou, and colleagues identified a novel mechanism by which PTEN loss induces aberrant phosphorylation of PI3Kβ at tyrosine 962. This event triggered the formation of an oncogenic EPHA2–SRC–PI3Kβ signaling complex. Targeting this phosphorylation, either genetically or with dasatinib, suppressed tumor growth in PTEN-deficient models. These findings position phospho-PI3Kβ Y962 as a druggable vulnerability and predictive biomarker, offering a strong rationale for new therapeutic strategies and biomarker-guided repurposing of dasatinib in PTEN-null solid tumors.See article, p. 521.Wang and colleagues show that the developmental timing of oncogenic mutations fundamentally shapes leukemia biology. Using genome engineering, the authors introduced the leukemia-driving fusion, NUP98::NSD1, into human blood stem cells from fetal, postnatal, pediatric, or adult stages. Fetal-derived stem cells transformed readily into aggressive leukemia, whereas later-stage cells became increasingly resistant. Single-cell analyses revealed that fetal-origin leukemia stem cells were more quiescent, metabolically distinct, and associated with poor patient outcomes. Importantly, these cells exhibited specific vulnerabilities that could be therapeutically targeted. This study establishes ontogeny as a key determinant of leukemic potential and provides a framework for developmental stage-informed precision therapy.See article, p. 541.Cellular senescence is a damage-induced program with contrasting tumor-suppressing and -promoting functions, the determinants of which are not fully understood. Zhou and colleagues found that senescence arises not only within tumor cells, but also in stromal populations in mouse and human prostate cancers. p21 marked senescent stromal cells with an inflammatory senescence-associated secretory phenotype (SASP) that promoted myeloid-mediated immune suppression and drove prostate tumorigenesis. Removal of stromal p21+ cells blocked tumor progression and activated T-cell immunity, potentiating anti–PD-1 immunotherapy in prostate cancer. These findings pave a path to target detrimental senescent cells in cancer to improve therapy outcomes.See article, p. 571.An important question in cancer pathogenesis is whether a genetic mutation is required for disease initiation, disease maintenance, or both. Here, Köhnke, Karigane, and colleagues examined this question in human acute myeloid leukemia (AML), where DNMT3A R882 missense mutations often arise early. They developed CRISPR-based methods to prospectively correct DNMT3A R882 mutations directly in primary patient cells. Using this approach, they find that DNMT3A R882 mutations were necessary for AML initiation and increased leukemia stem cell frequencies but were largely dispensable for maintenance. These findings disentangle initiation and maintenance roles of DNMT3A R882 mutations and showcase prospective functional cancer genetics in primary human cells.See article, p. 592.