Tianyu Tao

The efficacy of immunotherapy in colorectal cancer (CRC) is frequently limited by an immunosuppressive tumor microenvironment. Here, we identify exonuclease/endonuclease/phosphatase domain‐containing protein 1 (EEPD1), a gatekeeper of homologous recombination (HR) repair, as a key driver of this immune exclusion. Downregulation of EEPD1 profoundly compromises HR in CRC cells, which curtails their proliferative and metastatic capacities in vitro and in vivo. Mechanistically, EEPD1 deficiency fuels genomic instability, leading to cytosolic DNA accumulation and activation of the cGAS‐STING‐type I interferon axis. This cascade promotes dendritic cell maturation, skews macrophages toward a proinflammatory M1 phenotype, and enhances tumor‐associated antigen presentation, culminating in robust CD8 ⁺ T cell activation and cytotoxicity. Our findings elucidate a direct mechanism by which targeting EEPD1 sensitizes CRC to anti‐PD1 immunotherapy. Our work establishes EEPD1 as a promising therapeutic target to overcome immune checkpoint blockade resistance in colorectal cancer.

How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species–NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the m⁶A-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize ATF4 mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER–ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.

Figure S5 shows Hyp metabolism regulates glutathione metabolism and ferroptosis through Hyp-mediated iron accumulation

Figure S3 shows effects of cell death inhibitors on breast cancer bone metastasis

Supplementary Table S1 presents the baseline characteristics of the breast cancer patients included in the analysis.

Figure S1 shows Hyp metabolism regulates tumor cell adhesion and Hyp metabolism

Supplementary Table S3 lists the primer sequences used in this study.

Figure S7 shows hydroxyproline metabolism mediates metabolic regulation modulates YY1 acetylation and downstream signaling

Supplementary Table S2 shows the correlation between PRODH2 expression and clinicopathological characteristics in breast cancer patients.

Figure S6 shows co-culture system regulates IL-8 secretion and SLC7A11 expression