Major Finding: The liver X receptor (LXR) pathway drives intestinal regeneration and limits tumorigenesis. Concept: Transcriptomic and pharmacologic studies define a CYP27A1–LXR–TLS signaling axis in intestinal repair.   Impact: This study delineates a critical node at the nexus between repair and tumorigenesis that may provide insights into mechanisms of controlled regeneration and underpin human colorectal cancer etiology.

Major Finding: A phase 1b trial demonstrated the safety of cretostimogene grenadenorepvec plus nivolumab in muscle-invasive bladder cancer (MIBC). Concept: Boosting immune checkpoint inhibition with oncolytic virotherapy enhanced antitumor immunity in part through tertiary lymphoid structure maturation. Impact: These clinical results warrant further investigation of oncolytic virotherapy and immune checkpoint inhibitors in MIBC.

Major Finding: Specialized fibroblasts promote T-cell infiltration and activation in lung tumors. Concept: Fibroblastic reticular cells provide a scaffold and activating environment for intratumoral CD8 + T-cells Impact: Promoting interconnected T-cell environments may be an effective treatment strategy for lung cancer.

Main Finding: A phase I clinical trial demonstrates the safety of GD2-targeted CAR T-cell therapy in H3K27M + diffuse midline glioma. Concept: H3K27M + diffuse midline gliomas express high levels of GD2, which enable CAR-mediated tumor regression. Impact: This supports the efficacy of CAR T-cell therapy in lethal solid tumors and warrants further clinical investigation.

Major Finding: Extrachromosomal DNA (ecDNA) confers fitness advantages during tumor progression and metastasis. Approach: ecDNA was assessed across multiple cohorts compiled across disease stage, treatment status, and time. Impact: This study suggests targeting processes that contribute to ecDNA formation and maintenance as a therapeutic strategy.

Major Finding: FastGlioma, an AI-based visual model, rapidly scores the degree of glioma infiltration in surgical samples. Concept: This approach represents a rapid, label-free surgical adjunct that may reduce the risk of residual disease. Impact: This study highlights the potential of FastGlioma as a surgical adjunct for the treatment of glioma and other cancers.

Major Finding: An inhibitor of E17K-mutant AKT1 exhibits selective antitumor efficacy without inducing hyperglycemia. Concept: A salicylaldehyde-based compound binds the mutant lysine, as endogenous Zn 2+ chelation sustains inhibition. Impact: This lysine-targeted therapeutic strategy may overcome the dose-limiting toxicities of AKT inhibition.

Major Finding: A dual function supracluster was engineered to increase radiosensitivity and antitumor immunity. Concept: Gold supraclusters carrying siRNA against LGALS1 (galectin-1) reshaped the immune milieu and bolstered the abscopal effects of irradiation. Impact: Combining radiosensitizing agents and immune checkpoint targeting may reduce systemic tumor burden.

Major Finding: Therapy-resistant leukemia stem cells arise from RAS -mutant granulocyte-monocyte progenitor cells. Concept: RAS -mutant leukemia stem cells drive monocytic disease with altered expression of BCL2 family genes. Impact: Patients with RAS -mutant leukemia may not benefit from venetoclax-based combination therapies.

Major Finding: APOBEC3-associated mutagenesis and ecDNA formation coordinately drive urothelial cancer evolution. Concept: ecDNA events enable adaptive resistance to chemotherapy. Impact: This study delineates urothelial cancer evolution and proposes targeting CCND1 ecDNA amplification.

Major Finding: Antitumor T cells are recruited to intracranial metastases through ICAM-1 + peritumoral venous vessels (PVV). Concept: PVVs mediate T-cell recruitment and motility, which can be enhanced by immune checkpoint blockade. Impact: This study reveals PVVs as a primary site of T-cell extravasation and informs immunotherapeutic development.

Major Finding: AKT and EZH2 inhibitors synergistically induce apoptosis and regression in triple negative breast cancer (TNBC). Concept: The combination drives luminal differentiation that sensitizes TNBC to involution-associated cell death. Impact : This study proposes the potential clinical benefit of an AKT/EZH2-targeted therapeutic strategy in TNBC.

Major Finding: ASXL1 regulates T-cell terminal differentiation and exhaustion during chronic antigen exposure. Concept: Disruption of ASXL1 alters histone ubiquitination to promote a stem-like effector phenotype in T cells. Impact: Targeting ASXL1 in T cells may improve patient responses to immunotherapy.

Major Finding: Spatial profiling reveals site-specific activity of tertiary lymphoid structures (TLS) in ovarian cancer. Concept: Cancer-associated mesenchymal stem cells block the antitumor activity of TLS located within the ovary. Impact: This study highlights ovarian TLS heterogeneity and develops a gene signature for patient stratification.

Major Finding: TET2 deficiency drives chromatin remodeling in leukemia by enabling MBD6-dependent H2AK119ub removal. Concept: Loss of TET2-mediated RNA 5-methylcytosine (m 5 C) oxidation enhances MBD6 recruitment to chromatin-associated RNA (caRNA). Impact: Targeting MBD6 and m 5 C on caRNA may be an effective strategy in treating TET2 -mutant leukemia.

Major Finding: Alveolar macrophages (AM) induce dormancy in early disseminated cancer cells (DCC) in the lung. Concept: TGF-β2-TGF-βRIII signaling mediates DCC dormancy and is subverted during resistance in later stages. Impact: This study highlights a heterotypic cell–cell interaction that may be leveraged for therapeutic benefit.

Main Finding: Age-associated increases in midkine rewire luminal progenitor cells and promote tumorigenesis. Concept: Midkine exacerbates the age-dependent increase in breast cancer risk by activating PI3K–AKT–SREBF1. Impact : This study proposes midkine as a potential therapeutic target and functional biomarker in breast cancer.

Main Finding: A bivalent molecule that links CDK9 and BCL6 enables CDK9-dependent reactivation of apoptotic genes. Concept: CDK-TCIP1 brings CDK9 to BCL6 target genes, where CDK9 phosphorylates Pol II and promotes transcription. Impact : This study demonstrates that kinase activity can be redirected to elicit cancer cell–specific killing.

Major Finding: CTLA4 inhibition overcomes STK11 / KEAP1 mutation-driven resistance to anti PD-(L)1 immunotherapy. Concept: Dual CTLA4/PD-(L)1 blockade engages CD4 + T cells and antitumor myeloid cells to hinder tumor growth. Impact: Patients with STK11 / KEAP1 -mutant lung cancer, in particular, may benefit from dual immunotherapy.

Main Finding: Circulating tumor DNA (ctDNA)–guided targeted therapy improves survival outcomes in advanced solid tumors. Concept: ctDNA profiling guides effective therapy decisions and provides clinically relevant readouts of heterogeneity. Impact : This study supports the clinical benefit of ctDNA-guided therapies in the treatment of advanced solid cancers.