Metastasis, a major cause of cancer-related mortality worldwide, frequently occurs early in the diagnosis of lung adenocarcinoma (LUAD). However, the precise molecular mechanisms governing the aggressive metastatic behavior of LUAD remain incompletely understood. In this study, we present compelling evidence indicating that the long noncoding RNA linc01703 is significantly downregulated in metastatic lung cancer cells. Intriguingly, in vivo experiments revealed that Linc01703 exerted a profound inhibitory effect on lung cancer metastasis without discernible impact on the in vitro proliferation or invasion capacities of LUAD cells. Mechanistically, Linc01703 enhanced the interaction between Rab27a, SYTL1, and CD81, consequently promoting the secretion of CD81⁺ exosomes. These exosomes, in turn, suppressed the infiltration of immune cells within the tumor microenvironment, thereby impeding LUAD metastasis. Importantly, our analysis of lung cancer tissues revealed a correlation between reduced CD81 expression and an unfavorable patient prognosis. Collectively, our findings suggest that Linc01703 functions as a metastasis suppressor by facilitating the secretion of CD81⁺ exosomes through the formation of the Rab27a/SYTL1/CD81 complex.

Breast cancer frequently metastasizes to the bone, but treatment options for bone metastatic breast cancer are limited. Amino acid metabolism is reprogrammed in the bone metastatic microenvironment, suggesting that it could represent a therapeutic vulnerability. In this study, we focused on the metabolism of hydroxyproline (Hyp), a key amino acid resulting from bone collagen degradation, which serves as a critical biomarker for bone metastases. Proline dehydrogenase 2 (PRODH2), the primary enzyme involved in Hyp metabolism, was significantly upregulated in clinical samples from breast cancer bone metastases. Notably, PRODH2-mediated Hyp metabolism drove osteoclast differentiation, enhancing collagen degradation and promoting breast cancer bone metastasis in vivo. Furthermore, PRODH2 facilitated tumor cell viability and osteoclast differentiation by upregulating the ferroptosis inhibitor SLC7A11 and the bone metastasis–related factor CXCL8 (IL8), respectively. Intriguingly, Hyp metabolism catalyzed by PRODH2 generated acetyl-CoA, which enhanced YY1 acetylation and thereby transcriptionally activated both SLC7A11 and IL8. Importantly, treatment with a PRODH2 inhibitor effectively disrupted the bone metastatic cascade. Together, these results reveal that collagen degradation from osteolysis produces Hyp that reinforces osteoclast differentiation and metastasis, creating a vicious cycle. Identification of the role of the PRODH2–SLC7A11–IL8 axis in promoting breast cancer bone metastasis suggests potential therapeutic strategies to improve patient outcomes. Significance: In the bone microenvironment, osteolysis increases PRODH2-mediated hydroxyproline metabolism that drives osteoclast differentiation and suppresses breast cancer cell ferroptosis, which can be reversed by targeting PRODH2 to suppress metastatic progression.

Clusterin (CLU) is a heterodimeric glycoprotein that has been detected in diverse human tissues and implicated in many cellular processes. Accumulating evidence indicates that the expression of secreted CLU correlates with the progression of cancers. However, the molecular mechanisms underlying its tumor-suppressive roles are incompletely uncovered. In this study, we demonstrate that precursor CLU is widely downregulated in lung cancer tissue, in which secretory CLU proteins are slightly decreased. Impressively, overexpressing CLU potently inhibits the migration, invasion and metastasis of lung cancer cells, whereas silencing CLU promotes this behavior; however, it appears that secretory CLU fails to exert similar anti-metastatic effects. Interestingly, the cytoplasmic precursor CLU binds ROCK1 to abrogate the interaction between ROCK1 and ERK and impair ERK activity, leading to the suppression of lung cancer invasiveness. Meanwhile, the expression of CLU was remarkably diminished in lung cancer bone metastasis loci when compared with subcutaneous tumors in the mouse model and hardly detected in the bone metastasis loci of lung cancer patients when compared with the primary. These findings reveal a novel insight into the function and regulation of cytoplasmic CLU in lung cancer, which might be a potential target for the diagnosis and treatment of metastatic lung cancer.

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.

Breast cancer frequently metastasizes to the bone, but treatment options for bone metastatic breast cancer are limited. Amino acid metabolism is reprogrammed in the bone metastatic microenvironment, suggesting that it could represent a therapeutic vulnerability. In this study, we focused on the metabolism of hydroxyproline (Hyp), a key amino acid resulting from bone collagen degradation, which serves as a critical biomarker for bone metastases. Proline dehydrogenase 2 (PRODH2), the primary enzyme involved in Hyp metabolism, was significantly upregulated in clinical samples from breast cancer bone metastases. Notably, PRODH2-mediated Hyp metabolism drove osteoclast differentiation, enhancing collagen degradation and promoting breast cancer bone metastasis in vivo. Furthermore, PRODH2 facilitated tumor cell viability and osteoclast differentiation by upregulating the ferroptosis inhibitor SLC7A11 and the bone metastasis–related factor CXCL8 (IL8), respectively. Intriguingly, Hyp metabolism catalyzed by PRODH2 generated acetyl-CoA, which enhanced YY1 acetylation and thereby transcriptionally activated both SLC7A11 and IL8. Importantly, treatment with a PRODH2 inhibitor effectively disrupted the bone metastatic cascade. Together, these results reveal that collagen degradation from osteolysis produces Hyp that reinforces osteoclast differentiation and metastasis, creating a vicious cycle. Identification of the role of the PRODH2–SLC7A11–IL8 axis in promoting breast cancer bone metastasis suggests potential therapeutic strategies to improve patient outcomes.Significance:In the bone microenvironment, osteolysis increases PRODH2-mediated hydroxyproline metabolism that drives osteoclast differentiation and suppresses breast cancer cell ferroptosis, which can be reversed by targeting PRODH2 to suppress metastatic progression.