Nanobodies in precision oncology from target recognition to tumor-state-matched therapy

Nanobodies, the variable domains of camelid heavy-chain-only antibodies, are increasingly viewed as more than compact affinity reagents and are being developed as versatile components of precision oncology. Their small size, high stability, convex paratopes and ease of genetic or chemical engineering create a pharmacological design space that differs from that of conventional monoclonal antibodies. These properties can support rapid lesion access, rapid systemic clearance, modular multivalency, fusion to proteins or incorporation into cell-based recognition systems, and conjugation to radionuclides, cytotoxins, photosensitizers and nanocarriers. In this review, we propose that nanobody development in oncology is shifting from a target-centric approach toward tumor-state-matched pharmacology. We organize the field around six linked domains: molecular imaging and patient stratification, payload delivery and targeted therapy, immune engineering and checkpoint modulation, tumor microenvironment targeting, target blockade and degradation, and translational evidence standards for clinical implementation. Across these areas, precision is not defined by target positivity alone. It depends on alignment among target accessibility, VHH format, pharmacokinetics, payload mechanism, the tumor microenvironment and longitudinal biomarker readouts. We also outline the evidence needed to advance nanobody platforms from well-characterized preclinical constructs toward clinical use. These requirements include lesion-level imaging, format-specific pharmacology, mechanistic validation, safety and CMC assessment, and clinical trial designs in which VHH-derived readouts are linked to treatment decisions. This framework may help distinguish settings in which VHHs offer a practical advantage from those better served by other modalities. Nanobodies in precision oncology: from target recognition to tumor-state-matched therapy. This schematic summarizes the proposed tumor-state-matched framework for VHH-based oncology. VHH modules can support molecular imaging and patient stratification, payload delivery, immune engineering, tumor-microenvironment targeting, target blockade, cell-state control and degradation, and translational evidence generation. Together, these functions form a conceptual, hypothesis-generating adaptive loop linking lesion-level information with format selection, therapeutic intervention, monitoring and clinical decision-making. VHH, variable domain of a camelid heavy-chain-only antibody; TME, tumor microenvironment; CAFs, cancer-associated fibroblasts; CAR-NK, chimeric antigen receptor natural killer cell; CAR-T, chimeric antigen receptor T cell; ECM, extracellular matrix; NDC, nanobody-drug conjugate; NK, natural killer cell; PET, positron emission tomography; SPECT, single-photon emission computed tomography.