Selected Articles from This Issue

Alterations in protein glycosylation are a well-known hallmark of cancer. MUC1, a highly glycosylated protein that provides a protective mucous barrier to epithelial cells, is aberrantly glycosylated in various cancers as tumor-associated mucin-1 (TA-MUC1). Here, Takano and colleagues designed DS-3939a, a novel TA-MUC1 targeting antibody-drug conjugate (ADC) with a potent topoisomerase I inhibitor DXd as its payload. DS-3939a exhibited highly potent anti-tumor activity against various patient-derived xenograft models spanning multiple cancer types. Moreover, DS-3939a induced regression in tumors even after their treatment with clinically approved ADCs. These data motivate us toward further clinical investigation of DS-3939a in multiple cancers.Targeting SUMOylation has emerged as a powerful strategy to strenghten anti-tumor immunity. Here, Hallal and colleagues demonstrate that the SUMOylation inhibitor TAK-981 (subasumstat) potently activates NK cells from both healthy donors and Acute Myeloid Leukemia (AML) patients. TAK-981 enhances NK-cell degranulation, inflammatory cytokine secretion, and cytotoxicity against AML cells, and improves the anti-leukemic efficacy of adoptively transferred NK cells in vivo. Mechanistically, TAK-981 rapidly induces interferon-β secretion—primarily through a non-canonical pathway—leading to autocrine and paracrine NK cell activation. These findings highlight SUMOylation inhibition as a promising strategy to potentiate NK cell-based immunotherapies and counter immune suppression in AML.This study addresses the unmet need for effective targeted therapies in pediatric solid tumors by evaluating trastuzumab deruxtecan (T-DXd), a HER2-directed ADC whose activity in low-HER2 adult cancers suggested potential relevance in pediatric tumors with variable HER2 expression. Burke and colleagues observed significant antitumor activity across diverse pediatric histologies, including HER2-negative models, indicating that responses did not correlate with HER2 levels. Comparable activity between T-DXd and an isotype-matched control ADC supported substantial non–HER2-mediated activity. These findings highlight HER2’s limitations in pediatric tumors as a predictive biomarker and support biomarker-agnostic ADC development in pediatric cancer.