Jianwei Xu

Liver metastasis is associated with reduced benefit from immune checkpoint inhibitors (ICIs) in several gastrointestinal cancers, yet the background liver status is rarely considered in immunotherapy biomarker studies. Here, we examine whether metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) may alter the immune environment of liver metastases and affect ICI efficacy. The available evidence is strongest, and most mechanistic, for colorectal liver metastasis and derives largely from preclinical models; it is emerging for pancreatic ductal adenocarcinoma and limited for gastric and biliary tract cancers. MASLD and MASH should not be treated as interchangeable: simple steatosis, active steatohepatitis, fibrosis, and cirrhosis represent distinct liver conditions with different possible effects on hepatic seeding and immune-cell access. Early steatohepatitic inflammation may promote hepatic colonization through lipid availability, hepatocyte stress, and myeloid-cell recruitment, whereas advanced fibrosis can reduce initial colonization while impairing lymphocyte access to established lesions. ICI efficacy requires viable tumor-reactive T cells, relief from myeloid-cell suppression, and direct tumor-T-cell contact; MASLD- and MASH-related liver changes may interfere with each of these requirements through mechanisms beyond checkpoint-ligand expression alone. We distinguish T-cell exhaustion from liver metastasis-associated T-cell deletion, and highlight macrophage-mediated elimination of tumor-specific CD8-positive T cells, myeloid chemokine signaling-driven suppressor-cell recruitment, and stromal remodeling as candidate mechanisms, supported mainly by preclinical evidence, that may reduce ICI response. These mechanisms remain unvalidated as predictors of ICI response in cohorts with MASLD/MASH staging. Future studies should assess liver fat, inflammatory activity, fibrosis stage, tumor genotype, and ICI outcomes in the same patients to test whether MASLD/MASH stage is associated with differential benefit.

Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, limiting the efficacy of immunotherapy. T-cell regulation plays a pivotal role in anti-tumor immunity. However, the prognostic value and therapeutic implications of T-cell regulation-related genes (TRGs) in PC remain largely unexplored. This study aims to construct a TRG-based risk model and validate key therapeutic targets. Methods: Transcriptomic profiles and clinical data were retrieved from TCGA and GEO databases. Non-negative Matrix Factorization (NMF) clustering was performed to identify molecular subtypes. A prognostic risk signature was constructed using LASSO regression analysis. The immune landscape was evaluated via ssGSEA, CIBERSORT and TIDE algorithms. A nomogram was established to predict overall survival, and drug sensitivity was assessed based on IC50 estimation. Crucially, the expression of the key signature gene IL1RN was validated in clinical tissues using qRT-PCR, Western Blot, and immunohistochemistry (IHC). Its function in T-cell mediated cytotoxicity was further verified using co-culture assays. Results: Two distinct molecular subtypes were identified, with Cluster 1 exhibiting an immune-hot phenotype and superior survival. A robust risk model was constructed and validated, serving as an independent prognostic factor. High-risk patients were characterized by an immune-excluded phenotype but showed higher sensitivity to chemotherapeutic agents like Gemcitabine. Experimental validation confirmed that IL1RN was significantly upregulated in PC tissues. Functionally, knockdown of IL1RN significantly enhanced the cytotoxicity of T cells against pancreatic cancer cells in vitro . Conclusion: We constructed a novel TRG-based prognostic signature that can serve as an auxiliary tool for clinical prognostic evaluation in pancreatic cancer. Furthermore, we validated IL1RN as a critical mechanism of immune resistance. IL1RN is expected to become a novel target for pancreatic cancer immunotherapy, providing experimental evidence for the stratified treatment of PC.

Immune checkpoint inhibitors targeting programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) encounter significant clinical hurdles, primarily stemming from the high incidence of acquired resistance. To address these challenges, researchers have investigated second-generation targets like lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). However, these alternatives face limitations: LAG-3 necessitates PD-1 co-blockade for optimal efficacy, while TIM-3 inhibitors face delays in clinical translation due to restricted cellular expression patterns. In contrast, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) emerges as a promising option by bridging these gaps through its wide cellular distribution and synergistic mechanisms. This is attributed to its prevalent expression in T cells and natural killer (NK) cells, its ability to inhibit CD226 phosphorylation via the CD155/CD112 pathway, its synergistic reversal of T-cell exhaustion with PD-1, and its capacity to overcome drug resistance. Recent clinical trials have shown that TIGIT monotherapy yields modest responses, while combinations with PD-1 inhibitors exhibit enhanced tumor control in conventional malignancies, surpassing standard PD-1/CTLA-4 or PD-1/chemotherapy protocols. Future research priorities include validating predictive biomarkers, optimizing dosing schedules to prevent resistance development, and devising multi-checkpoint strategies. This review systematically assesses the therapeutic synergy centered on TIGIT, offering a translational framework for surmounting tumor diversity and immunotherapy resistance through advanced combinatorial approaches.

Background It is widely believed that the prerequisite for safely performing enucleation is that the distance between the tumor and the main pancreatic duct (MPD) is at least 2–3 mm. However, enucleating a deep pancreatic tumor adjacent to the MPD remains challenging, particularly when exposure or repair of the MPD is necessary. This study reported our initial experience with this procedure and demonstrated the feasibility and safety of the MPD exposure or repair. Methods Patients who underwent laparoscopic enucleation (LapEN) with exposing the MPD from January 2017 to August 2023 were collected and analyzed in this retrospective cohort study. Data from procedures of laparoscopic middle pancreatectomy (LMP) and LapEN for superficial tumors were collected for comparative analyses. Results A total of 26 patients were enrolled, 27 tumors were enucleated. Tumor located in the pancreatic head and neck (n = 20), and the body (n = 7). The mean tumor size, operating time, and blood loss were 2.3 cm, 163 min, and 63 ml, respectively. MPD injuries occurred in 8 cases due to the need for complete tumor resection, which were repaired or reconstructed using 6–0 PDS-II with or not inserting a plastic stent. 10 cases (38.5%) developed surgical‐related complications, seven (26.9%) were classified as Clavien-Dindo grade I, and three (11.5%) were Clavien-Dindo grade IIIa. Biochemical leakage occurred in 16 cases (61.5%), clinically relevant pancreatic fistula (CR-POPF) occurred in 10 cases (38.5%). Two patients (7.7%) experienced post-pancreatectomy hemorrhage. Further analyses indicated LapEN with MPD exposure had a longer operating time and higher incidence of CR-POPF compared to LapEN for superficial tumors, but a shorter operating time and less blood loss compared to LMP (P < 0.05). Conclusion Laparoscopic enucleation with exposing the MPD is feasible and safe with the support of precise preoperative assessments, meticulous intraoperative dissection, well familiarity with the anatomy of the MPD, and excellent surgical skills.

Background: More and more patients with pancreatic cancer (PC) received neoadjuvant therapy (NAT) and then underwent radical pancreatectomy. However, the benefit of adjuvant chemotherapy (AC) for these patients is still controversial. This study is designed to determine the benefits of postoperative AC for patients with PC undergoing NAT and radical resection.Methods: We conducted a comprehensive search of the PubMed, Embase, Web of Science, and Cochrane Library databases, covering the period from their inception until 10 September 2023. Our analysis focused on the assessment of overall survival (OS) and recurrence-free survival (RFS) through meta-analysis. The fixed-effects model and the random-effects model were used to process the data. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were employed to determine the necessary of administering AC for patients with PC who have undergone NAT and radical resection. We retrieved 3,063 search results, of which 3,048 were excluded because of duplication or after applying our inclusion and exclusion criteria.Results: A total of 15 studies with 21,113 patients (7,794 patients in the AC group and 13,319 in the non-AC group) were included, all of which reported OS, and three studies reported disease-free survival (DFS)/tumor-specific survival (CSS)/RFS. The final results showed that AC significantly improved OS and DFS/CSS/RFS in patients with PC who underwent pancreatectomy after NAT [OS: HR = 0.80, 95% CI (0.75∼0.86), P < 0.00001, I² = 48%; DFS/CSS/RFS: HR = 0.53, 95% CI (0.41~0.69), P < 0.00001, I² = 0%]. Furthermore, we performed subgroup analyses and demonstrated that AC provided a significant survival benefit for patients with PC after NAT and resection regardless of the tumor size [<2-cm subgroup: HR = 0.72, 95% CI (0.5∼0.94), P = 0.01; ≥2-cm subgroup: HR = 0.79, 95% CI (0.65∼0.96), P = 0.02] and the margin status [R0 subgroup: HR = 0.83, 95% CI (0.77∼0.88), P < 0.00001; R2 subgroup: HR = 0.75, 95% CI (0.61∼0.92), P = 0.007]. AC also benefited the patients with a stage N0 [HR = 0.79, 95% CI (0.74~0.84), P < 0.00001], N1 [HR = 0.78, 95% CI (0.72∼0.85), P < 0.00001], or poorly/undifferentiated tumor [HR = 0.76, 95% CI (0.66∼0.87), P < 0.0001] in survival but not in patients with a stage N2 [HR = 0.69, 95% CI (0.43∼1.09), P = 0.11] or well/moderately differentiated tumor [HR = 0.97, 95% CI (0.66∼1.42), P = 0.87].Conclusions: Although AC showed survival benefit for patients with PC undergoing radical pancreatectomy after NAT, we still need to consider the lymph node stage and the degree of differentiation of the tumor when we gave AC to a patient. High-quality prospective randomized controlled studies are required to well disclose the value of AC in patients with PC undergoing radical pancreatectomy after NAT.Systematic review registration: https://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42023461365.

Background: Pancreatic metastasis is rare. Its characteristics have primarily been described in autopsy studies and case reports, which may not accurately reflect the actual clinical profiles. Moreover, few studies have addressed the prognostic feature in patients with pancreatic metastasis. Methods: Cases of pancreatic metastases that were diagnosed by the multidisciplinary tumor board from September 2013 to July 2023 at our hospital were collected and analyzed. Results: A total of 77 cases were collected. The most common primary tumor sites were the lung (35.1%) and kidney (23.4%). Clear cell renal carcinoma (CCRC) accounted for 23.4% of cases, making it the most common histological type, followed by small cell lung cancer (SCLC, 16.9%). Among the cases, 36.4% (28 cases) presented with organ-related symptoms, and 70.4% (57 cases) were solitary metastases. Metachronous metastases accounted for 70.1% (54 cases), with an average interval of 62.7 ± 74.4 months between the diagnosis of the primary tumor and metastasis. The overall survival (OS) of the collected cases was 42 months. The overall survival (OS) for all cases was 42 months. OS varied by primary tumor type, with pancreatic metastases secondary to lung, kidney, digestive tract, and gynecological cancers showing OS of 23, 81, 11, and 32 months, respectively. Subgroup analysis indicated that 15 cases secondary to the CRCC were metachronous with an average interval of 132.4 ± 83.9 months from initial diagnosis to metastasis, who had an OS of 80 months. Radical resection was performed in 10 of these cases, increasing the OS to 91 months. Conclusion: Pancreatic metastasis was uncommon and imperceptible. The prognosis of patients depended on the primary tumor type and the timing of metastasis. Pancreatic metastases secondary to CCRC were the most frequent and had the most favorable prognosis. Radical resection of the metachronous metastases prolonged survival. This study described the real-world clinical profiles of pancreatic metastases, providing valuable insights to reduce misdiagnosis and guide treatment decisions.

Background: As a fatal disease, the mechanism of pancreatic cancer is unclear. Urothelial carcinoma antigen 1(UCA1), a long noncoding RNA (lncRNA) that was first reported in bladder cancer, acts as an oncogene. However, the regulatory role and mechanism of UCA1 in pancreatic cancer remain unknown. This study aims to investigate the expression level and prognostic value of UCA1 in pancreatic cancer tissues, the effects and mechanism of UCA1 in regulating cell proliferation, apoptosis and metastasis.Methods: UCA1 expression levels in tissues were detected by in situ hybridization (ISH) and the prognostic value was evaluated by univariate and multivariate survival analysis. For in vitro experiments, proliferation was evaluated by a cell count kit assay, Edu experiments, and a clone formation assay. Apoptosis was evaluated by fluorescence-activated cell sorting flow-cytometry. Cell migration and invasion capacities were detected by wound healing and transwell assays. Western blots were performed to detect apoptotic associated molecules and epithelial-mesenchymal transition (EMT) markers. For the in vivo experiment, subcutaneous transplantation models of pancreatic cancer in nude mice were established to observe the tumor growth. The regulatory mechanism of UCA1 was explored by proteomics, bioinformatic analysis, luciferase reporter assays, and rescue experiments.Results: ISH staining revealed that UCA1 levels between cancer tissues (n=94) and tumor-adjacent tissues (n=73) did not show significant differences. Survival analysis indicated that high expression of UCA1 was an unfavorable prognosis factor for pancreatic cancer. Downregulation of UCA1 by siRNA significantly inhibited cell proliferation, decreased the capacities of cell migration and invasion, induced cell apoptosis, and inhibited EMT. Furthermore, we demonstrated that UCA1 positively regulated the expression of BRCC3 by inhibiting miR-582-5p. Rescue experiments indicated that either inhibiting the expression of miR-582-5p or enhancing expression of BRCC3 could partly attenuate the antitumor effects of downregulation of UCA1.Conclusion: UCA1 acted as an oncogene in pancreatic cancer by partly regulating miR-582-5p/BRCC3, which could be a new therapeutic target for pancreatic cancer.