Targeting the MYC-SUMO axis with TAK-981 reverses immune suppression and restores antigen presentation in osteosarcoma

Background: Osteosarcoma (OS), the most common primary bone cancer in adolescents, remains difficult to treat due to aggressive growth, early metastasis, and poor response to immunotherapy. About 20-30% of OS harbor 8q24 amplification, causing MYC overexpression and an immune-cold tumor microenvironment (TME). To investigate MYC-driven immune evasion, we generated an osteoblast-specific Myc-knockin GEMM and performed complementary mechanistic studies. Methods: The Myc-knockin model was characterized through histopathology, growth kinetics, immune profiling (flow cytometry, IHC), Western blotting, and RNA-seq. Antigen-presentation machinery (APM) gene expression was assessed in GEMM tumors, OS PDXs, and public datasets. MYC dependence was tested using dTAG degradation and siRNA knockdown. Because MYC is linked to SUMO-dependent repression, we examined the SUMO pathway using the SAE inhibitor TAK-981 and SAE1 knockdown. SUMO-interactome profiling (SUMO-IP/MS) identified MYC-associated SUMO substrates. Results: The MYC-knockin GEMM developed rapidly progressive and highly metastatic OS that transcriptionally resembled MYC-high human OS. MYC activation produced a strongly immunosuppressive TME with reduced CD45⁺ cells and broad APM repression. MYC loss restored APM expression, establishing MYC as a key inhibitor of antigen presentation. SUMOylation machinery (SUMO1/2, SAE1/2, UBC9) was elevated in MYC-high models and inversely correlated with APM. TAK-981 showed potent MYC-selective cytotoxicity in vitro, with MYC-high cells far more sensitive than MYC-low counterparts across mouse and PDX lines. TAK-981 also reduced proliferation, migration, and sphere formation. In vivo, TAK-981 significantly suppressed tumor growth across syngeneic and PDX models. Transcriptomics revealed reduced MYC targets, EMT, glycolysis, and G2/M signaling, alongside induction of IFN-alpha/gamma pathways, inflammatory responses, and APM genes. SUMO-IP/MS identified MYC-regulated SUMO-interacting proteins, including G3BP1/2, TARDBP, EIF3D, and PSMD4, implicating SUMO-dependent immune-evasion mechanisms. Combining TAK-981 with a STING agonist produced synergistic tumor control, achieving near-complete responses. Conclusions: MYC drives immune suppression in OS through SUMO-dependent repression of antigen-presentation and innate immune pathways. Targeting the MYC-SUMO axis with TAK-981 converts the TME from immune-cold to immune-inflamed and enhances immunotherapy responses, supporting TAK-981-based combinations as a promising strategy for MYC-driven OS.