Vivek Subbiah. Nature Communications. (2025) 16:4972
Tissue-agnostic cancer therapies promise to revolutionize oncology by targeting moleculardrivers. Sledge et al.’s study of nearly 300,000 tumors found 21.5% with tissue-agnostic indications. Despite nine FDA approvals, real-world implementation challenges persist. Progressdepends on universal genomic testing, an oncogenomic-savvy workforce, innovative trials, updated regulations, and real-world evidence to maximize potential. The oncology landscape has undergone a remarkable transformation with the emergence of tissue-agnostic therapeutic approaches1. At its core, the concept—treating cancer based on molecular drivers ratherthan tissue of origin—is both conceptually simple and clinically transformative Pembrolizumab made history in 2017 as the first tissue-agnostic therapy receiving accelerated approval for MSI-H/dMMR solid tumors in both adults and children. By 2023, it received full approval based on data from 504 patients with over 30 cancer types. The FDA has now approved nine tissue-agnostic therapies across three categories: targeted therapies (NTRK-fusions, BRAFV600E-mutations, RET-fusions), immunotherapies (MSI-H/dMMR, TMB ≥ 10 mutations/megabase), and an antibody-drug conjugate for HER2-positive tumors (immunohistochemistry 3+ expression). Cancer is fundamentally a genetic disease. The tissue-agnostic approach represents our journey toward truly personalized oncology, with its greatest value in expanding precision medicine access for patients with rare cancers and molecular alterations. As we advance, we must integrate scientific innovation with clinical pragmatism— embracing complexity while pursuing precision. Oncology is undergoing a seismic shift, with the future becoming molecular, not anatomical. This represents more than an academic distinction—it represents a fundamental reimagining of how we understand and treat cancer. AI methods are poised to identify more tissue-agnostic targets, and by focusing on cancer’s genetic drivers while respecting tissue-specific biology, we can move toward a more precise, effective, and compassionate approach—personalizing treatment one patient, one tumor, and one molecular profile at a time.
15 Apr, 2026