Metastasis is a leading cause of cancer-related deaths, with the liver being the most frequent site of metastasis in colorectal cancer. Previous studies have predominantly focused on the influence of the primary tumor itself on metastasis, with relatively limited research examining the changes within target organs. Using an orthotopic mouse model of colorectal cancer, single-cell sequencing was employed to profile the transcriptomic landscape of pre-metastatic and metastatic livers. The analysis focused on identifying cellular and molecular changes within the hepatic microenvironment, with particular emphasis on inflammatory pathways and immune cell populations. A neutrophil subpopulation with high Prok2 expression was identified, showing elevated levels in the pre-metastatic and metastatic liver. Increased infiltration of Prok2⁺ neutrophils correlated with poor prognosis in liver metastatic colorectal cancer patients. In the liver metastatic niche (MN), these neutrophils showed high App and Cd274 (PD-L1) expression, suppressing macrophage phagocytosis and promoting T-cell exhaustion. A Prok2⁺ neutrophil subpopulation infiltrated both pre-metastatic and macro-metastatic liver environments, potentially driving immunosuppression through macrophage inhibition and T-cell exhaustion. Targeting Prok2⁺ neutrophils could represent a novel therapeutic strategy for preventing liver metastasis in colorectal cancer patients.

Sodium methyldithiocarbamate (SMD) is one of the most abundantly used conventional pesticides in the United States. At dosages relevant to occupational exposure, it causes major effects on the immune system in mice, including a decreased resistance to sepsis. This lab has identified some of the mechanisms of action of this compound and some of the immunological parameters affected, but the global effects have not previously been assessed. The purpose of the present study was to conduct transcriptomic analysis of the effects of SMD on lipopolysaccharide-induced expression of mediators important in innate immunity and inflammation. The results revealed broad effects on expression of transcription factors in both branches of Toll-like receptor 4 (TLR4) signaling (MyD88 and TRIF). However, TLR3 and interferon signaling pathways were decreased to a greater extent, and assessment of the effects of SMD on polyinosinic polycytidylic acid–induced cytokine and chemokine production revealed that these responses mediated by TLR3 were indeed sensitive to the effects of SMD, with inhibition occurring at lower dosages than required to inhibit responses to other immunological stimuli tested in our previous studies. In the downstream signaling pathways of these TLRs, functional analysis also revealed that NF-κB activation was inhibited by SMD, as indicated by gene expression analysis and a reporter construct in mice. A previously unreported effect on luteinizing hormone and follicle-stimulating hormone pathways was also observed.

The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver premetastatic niche (PMN) formation. Clinically, elevated serum LRG1 levels are correlated with an increased risk of liver metastasis in patients and multiple mouse models. Mechanistically, LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophil accumulation, impairing the function of effector T cells and dendritic cells, and enhancing angiogenesis in the liver, thereby fostering a prometastatic landscape. Hepatocyte-specific ablation of LRG1 dampens premetastatic niche formation and significantly reduces the metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs). Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte–LRG1 axis that drives liver premetastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.

Triple‐negative breast cancer (TNBC) poses a significant challenge due to its high mortality rates, primarily attributed to resistance against chemotherapy regimens containing taxanes like paclitaxel. Thus, developing combinatorial strategies to override resistance is a pressing need. By taking advantage of a library screening with various kinase inhibitors, we found that the small‐molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Mechanistically, dual treatment with paclitaxel and enzastaurin resulted in efficient mitotic arrest and subsequent cell death by restoring AURKB expression. Further analysis revealed that the GCN2‐p‐eIF2α axis was responsible for the posttranscriptional accumulation of AURKB upon combinatorial treatment. Finally, we confirmed that combinatorial regimens synergistically suppressed tumour growth in vivo in mouse models. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic.

Identifying targets to enhance tumor immunity is an urgent need. Although nucleic acid sensors play critical roles in promoting tumor immune clearance, their exceptionally low mutation rate in cancers suggests potential unexplored roles in tumor progression. Here, we demonstrated that the RNA sensor MDA5 promotes immune evasion, and its high expression was strongly predictive of poor survival and resistance to immune checkpoint blockade (ICB) therapy in patients. Targeting MDA5 reshapes the tumor microenvironment, strengthening immune memory responses and enhancing effector CD8⁺ T cell activity. Mechanistically, MDA5 deficiency triggers UPR-driven immunogenic cell death (ICD) through induction of damage-associated molecular patterns (DAMPs), leading to enhanced dendritic cell-mediated antigen engulfment and T cell activation. Additionally, MDA5 loss primes the ASK1-JNK/P38 signaling pathway, sensitizing tumor cells to TNFα/IFNγ, further amplifying this process. Consequently, targeting MDA5 enhances the efficacy of ICB therapy across multiple cancer types, positioning it as a promising therapeutic target.

The efficacy of chemotherapy in colorectal cancer (CRC) is closely linked to its ability to remodel the tumor immune microenvironment (TIME), though the underlying molecular determinants remain incompletely defined. Here, we identified tumor‐cell intrinsic autophagy as a pivotal orchestrator of an immunologically active TIME, essential for chemotherapy response. We demonstrated that 5‐FU/Oxaliplatin treatment triggers autophagy‐dependent TIMP‐2 production, which restrains MMP‐2/9 activity and promotes intra‐tumoral accumulation of active CD8 ⁺ T cells. Disruption of this axis—through autophagy deficiency or loss of TIMP‐2—leads to CD8 ⁺ T cell exclusion and therapeutic resistance. Conversely, restoration of TIMP‐2 or co‐administration of MMP‐2/9 inhibitor successfully reinvigorated CD8 ⁺ T cells within the tumor and revived treatment efficacy. Mechanistically, autophagy‐mediated degradation of FBXW2 leads to the accumulation of C/EBPβ via the ubiquitin‐proteasome pathway, thereby driving transcriptional upregulation of TIMP‐2. Clinically, autophagy status and TIMP‐2 expression correlated with favorable immune profiles and improved clinical outcomes. These findings establish the autophagy–TIMP‐2 axis as a key determinant of chemotherapy‐induced immune remodeling and a potential target for enhancing therapeutic response and patient stratification in CRC.