Progress in targeting the untouchables: emerging approaches for hard-to-drug cancer targets.

Innovation in drug development is an evolving concept that can take many forms and is often confused with iteration, i.e. new versions of existing drug classes targeting familiar oncogenes. Yet meaningful innovation increasingly lies in translating approaches to historically 'untouchable' targets: transcription factors, tumor suppressors, and lineage-defining proteins, which have long resisted conventional pharmacologic approaches. At the European Society for Medical Oncology (ESMO) Targeted Anticancer Therapies (TAT) 2025 Congress, a growing body of early-phase trials has continued to test and refine this paradigm, showcasing first-in-human studies and novel modalities aimed at drugging long-deemed inaccessible sites. In this manuscript, we review key highlights from ESMO TAT and other pivotal drug development meetings and delve into targeting these so-called 'untouchable' targets. Organized by target class (KRAS, MYC, TP53, WNT) and modality [proteolysis-targeting chimeras (PROTACs), antibody-drug conjugates, bispecifics], we explore how translational frameworks, rational trial design, and platform-specific engineering are reshaping what is now clinically feasible in drug development. Finally, we present early-phase data from the most compelling trials and compounds and explore what remains to be achieved to move beyond proof of concept into clinically meaningful benefits for patients with cancer.