MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies.

The real-time detection of intracellular biological processes by encoded sensors has broad application prospects. Here, we developed a degron-based modular reporting system, the Device of Death Operation (DODO), that can monitor various biological processes. The DODO system consists of a “reporter”, an “inductor”, and a “degron”. After zymogen activation and cleavage, the degron will be released from the “reporter”, which eventually leads to the stabilization of the “reporter”, and can be detected. By replacing different “inductors” and “reporters”, a series of biological processes can be reported through various signals. The system can effectively report the existence of TEV protease. To prove this concept, we successfully applied the DODO system to report apoptosis in 2D and 3D cultures. In addition, the reporter based on degron will help to design protease reporters other than caspase.

The MYC oncoprotein drives aggressive tumor behavior across many cancer types, yet its intrinsically disordered structure has limited direct pharmacologic targeting. Building on our previous kinome-wide CRISPR screen, we identify the receptor tyrosine kinase EphB4 as a druggable synthetic-lethal vulnerability in MYC-driven cancers. Genetic ablation or pharmacologic inhibition of EphB4 selectively triggers robust apoptosis in MYC-activated normal cells and MYC-high triple-negative breast cancer (TNBC) cell lines, while sparing MYC-low counterparts. This apoptotic response is Bcl-2-sensitive and p53-independent, overcoming a major resistance barrier in TNBC. In vivo, EphB4 inhibition markedly suppresses MYC-driven tumor growth. Notably, co-targeting EphB4 and Bcl-2 with ABT-199 yields synergistic apoptosis and induces tumor regression in TNBC models. Mechanistically, EphB4 inhibition leads to the selective transcriptional repression of PSMB5, the β5 catalytic subunit of the proteasome, resulting in the impairment of proteasome activity and the induction of MYC-dependent apoptotic stress. This establishes an unexpected link between EphB4 signaling and proteostasis maintenance, a heightened dependency in MYC-overexpressing cells due to their elevated biosynthetic load. Targeting PSMB5 transcription, rather than its catalytic active site, also provides a potential strategy to circumvent or delay resistance to conventional proteasome inhibitors. Together, these findings define the EphB4-PSMB5 axis as a mechanistically distinct and therapeutically actionable vulnerability in MYC-high TNBC, positioning EphB4 inhibition as a promising approach to treat MYC-driven cancers.