Pan-modification proteomics: decoding tumor heterogeneity and guiding the next generation of precision oncology

Tumor heterogeneity is driven by genomic and transcriptomic variation, as well as by extensive protein diversification through post-translational modifications (PTMs), which generate distinct functional proteoforms. These combinatorial modifications reshape signaling, metabolism, and therapeutic response, adding a regulatory layer that conventional proteomics often fails to capture. Recent advances in mass spectrometry and open-modification analysis have enabled systematic profiling of pan-modification proteoforms. This emerging framework provides a deeper mechanistic basis for understanding and resolving tumor heterogeneity. This review explores the integration of multiple PTMs in shaping proteoform identity and the subsequent reprogramming of oncogenic signaling pathways. The impact of advanced analytical frameworks, such as top-down proteomics and spatially resolved mapping, on contemporary tumor biology is assessed. Additionally, we discuss the clinical implications of proteoform-centric biomarkers regarding therapeutic interventions and resistance. By reframing proteomic regulation in terms of pan-modification and proteoform diversity, this review outlines a foundational framework for next-generation precision oncology that interprets proteins not as single entities but as dynamic assemblies of functionally encoded molecular states.