In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in modulating the tumor immune microenvironment and the biological effect on the immune evasion of gastric cancer remains unclear. In this study, we found that forced expression of sLGMN in gastric cancer serum correlates with increased M2 macrophage infiltration in GC tissues and predicted resistance to anti-PD-1 immunotherapy. Mechanistically, gastric cancer cells secrete LGMN via binding to cell surface Integrin αvβ3, then activate Integrin αvβ3/PI3K (Phosphatidylinositol-4,5-bisphosphate3-kinase)/AKT (serine/threonine kinase)/mTORC2 (mammalian target of rapamycin complex 2) signaling, promote metabolic reprogramming, and polarize macrophages from the M1 to the M2 phenotype. Either blocking LGMN, Integrin αv, or knocking out Integrin αv expression and abolishing the LGMN/Integrin αvβ3 interaction significantly inhibits metabolic reprogramming and polarizes macrophages from the M1 to the M2 phenotype. This study reveals a critical molecular crosstalk between gastric cancer cells and macrophages through the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis in promoting gastric cancer immune evasion and resistance to anti-PD-1 immunotherapy, indicating that the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis may act as a promising therapeutic target.

Multidrug resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC). Although recent studies have reported that the multidrug resistance phenotype is associated with abnormal DNA methylation in cancer cells, the epigenetic mechanism underlying multidrug resistance remains unknown. Here, we reported that the level of 5-hydroxymethylcytosine (5-hmC) in human HCC tissues was significantly lower than that in adjacent liver tissues, and reduced 5-hmC significantly correlated with malignant phenotypes, including poor differentiation and microvascular invasion; additionally, loss of 5-hmC was related to chemotherapy resistance in post-transplantation HCC patients. Further, the 5-hmC level was regulated by ten-eleven translocation 2 (TET2), and the reduction of TET2 in HCC contributes to chemotherapy resistance through histone acetyltransferase P300/CBP-associated factor (PCAF) inhibition and AKT signaling hyperactivation. In conclusion, loss of 5-hmC induces chemotherapy resistance through PCAF/AKT axis and is a promising chemosensitivity prediction biomarker and therapeutic target for HCC patients.

Background: Liver metastasis represents the most common distant dissemination in gastric cancer (GC) but persists as a challenging condition to manage, and its driving molecular mechanisms remain poorly understood. This study aimed to uncover the key regulatory drivers of GC liver metastasis and explore their potential as therapeutic targets. Methods: Herein, we employed a multifaceted approach combining single-cell RNA sequencing, bulk transcriptomics, epigenomics analyses of GC primary tumors and normal adjacent tissues, paired liver metastasis, and circulating tumor cells, alongside in vitro and in vivo experimental validation, to investigate how metastatic GC cells spread to and adapt within the liver microenvironment. Results: We discovered that GC cells undergoing liver metastasis transcriptionally reprogrammed into a high plasticity state. This plasticity was mediated by the transcription factor CCAAT enhancer-binding protein beta ( CEBPB ), which activated liver metastasis-associated genes through enhancer reprogramming. Notably, CEBPB -driven reprogramming enhanced the metastatic potential of GC cells and enabled them to evade immune surveillance via interactions between cluster of differentiation 155 (CD155) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Blocking the CD155–TIGIT interplay inhibited liver metastasis and restored T cell cytotoxicity. Conclusions: Our study identifies CEBPB-mediated transcriptional and epigenetic reprogramming as a fundamental driver of GC liver metastasis. Our findings underscore the CEBPB / CD155 / TIGIT axis as a promising therapeutic target for liver-metastatic GC.

Immunotherapy and radiotherapy are important means for treating solid tumors. Both treatment methods can potentially cause neurologic injuries. Timely identification, diagnosis, and early treatment play a crucial role in the recovery from neurologic damage. This case report describes a 69-year-old woman with esophageal and oropharyngeal cancer who developed neurological complications after radiotherapy and immunotherapy. She experienced radiation-related motor impairment and symptoms returned after treatment with bevacizumab and corticosteroids. Later, she developed a rare demyelinating neuropathy, diagnosed as MOG antibody-associated disease (MOGAD), likely triggered by immune checkpoint inhibitors, which is a very rare adverse drug reaction. Her condition improved with cessation of immunotherapy and the administration of steroid pulse therapy. Despite treatment interruptions due to side effects, her survival period was favorable, suggesting that reduced-dose therapy in elderly patients may not diminish its antitumor effect. This case emphasizes the need for vigilance in recognizing rare complications and rational antitumor treatment intensity in geriatric oncology.