A Pan-Cancer Atlas of Metabolic Regulatory Circuitries Integrating Multi-Omic, Immune, and Clinical Dimensions

Background Metabolic reprogramming is a defining component of tumor progression, immune evasion, and susceptibility to regulated cell death, yet the organization of these processes across multi-omic, immune, and clinical dimensions remains unresolved. Results Here, we present a Pan-Cancer atlas of metabolic regulatory circuitries, reconstructed using OncoMetabolismGPS, a multi-omic analytical framework that systematically integrates transcriptomic, epigenomic, genomic, proteomic, phenotypic, immunological, and clinical axes across 33 tumor types. From 463,433 significant associations, we derived 241,415 omic-specific metabolic signatures and identified 24,796 metabolic regulatory circuitries defined by regulator–signature pairs exhibiting convergent or divergent behavior. Across cancers, divergent regulation predominated, particularly within immune-cold microenvironments, revealing a generalizable compensation logic that links metabolic activity with tumor phenotypes and patient outcomes. This atlas demonstrates that metabolic state operates as an n-dimensional regulatory architecture in which upstream non-coding RNAs modulate metabolic signatures in a context-dependent manner. All results are implemented in the OncoMetabolismGPS Shiny platform, which positions each signature within a multidimensional space spanning molecular, phenotypic, immune, and clinical attributes. Conclusions Together, this work introduces a unified, mechanistically grounded framework for interrogating metabolic regulatory circuitries in cancer and provides an openly accessible resource for exploring metabolic dependencies and therapeutic vulnerabilities.