Pancreatic cancer remains a challenging disease with limited treatment options, resulting in high mortality rates. The predominant approach to managing pancreatic cancer patients continues to be systemic cytotoxic chemotherapy. Despite substantial advancements in immunotherapy strategies for various cancers, their clinical utility in pancreatic cancer has proven less effective and durable. Whether administered as monotherapy, employing immune checkpoint inhibitors, tumor vaccines, chimeric antigen receptors T cells, or in combination with conventional chemoradiotherapy, the clinical outcomes remain underwhelming. Extensive preclinical experiments and clinical trials in the realm of pancreatic cancer have provided valuable insights into the complexities of immunotherapy. Chief among the hurdles are the immunosuppressive tumor microenvironment, limited immunogenicity, and the inherent heterogeneity of pancreatic cancer. In this comprehensive review, we provide an overview and critical analysis of current clinical immunotherapy strategies for pancreatic cancer, emphasizing their endeavors to overcome immunotherapy resistance. Particular focus is placed on strategies aimed at reshaping the immunosuppressive microenvironment and enhancing T cell-mediated tumor cell killing. Ultimately, through deeper elucidation of the underlying pathogenic mechanisms of pancreatic cancer and the refinement of therapeutic approaches, we anticipate breakthroughs that will pave the way for more effective treatments in this challenging disease.

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising therapy for irritable bowel syndrome (IBS). The aims of this clinical trial were to evaluate the influence of taVNS on autonomic functions, rectal sensation, and acetylcholine (Ach) levels and to explore potential mechanisms involving gut microbiota and metabolic profiles. METHODS: This study was a single-center, single-blind, randomized controlled trial executed at the First Affiliated Hospital of USTC, Anhui, China. Individual patients' constipation-predominant IBS (IBS-C)-related symptoms and mental health were assessed and scored using questionnaires at baseline and at week 4. Levels of serum Ach and nitric oxide, anorectal manometry, and heart rate variability were assessed both before and after the therapy. Fecal samples from each group were assessed to compare the gut microbiota, short-chain fatty acids, and gut microbiota-derived tryptophan metabolites. RESULTS: Between September 2023 and May 2024, 40 patients (n = 20 in both taVNS and sham-taVNS groups) completed the 4-week study by performing an intention-to-treat analysis. No differences in all parameters between taVNS and sham-taVNS groups at the baseline were found. The taVNS significantly improved the visual analog scale score (P < 0.001), IBS Severity Scoring System score (P < 0.001), weekly frequency of spontaneous bowel movements (P < 0.001), weekly frequency of complete spontaneous bowel movements (P = 0.004), Bristol Stool Form Scale score (P < 0.001), Hamilton Anxiety Scale score (P < 0.001), Hamilton Depression Scale score (P < 0.001), and IBS Quality of Life score (P < 0.001). Furthermore, taVNS improved rectal sensation in patients with IBS-C, including improvements in the threshold volume for initial sensation (P = 0.033), urge to defecate (P = 0.022), and rectoanal inhibitory reflex (P = 0.002). Moreover, taVNS elevated serum levels of Ach (P = 0.005) and reduced nitric oxide (P = 0.016) while also enhancing vagal activity (P < 0.001) as determined by spectral analysis of heart rate variability. Three patients in the taVNS group and 2 in the control group had adverse consequences, which were manageable. In addition, taVNS led to a significant rise in the level of the genus Bifidobacterium (P = 0.038) and increased levels of acetic (P = 0.003), butyric (P = 0.011), and propionic (P = 0.005) acids. It also decreased tryptophan metabolism content, including 3-hydroxyanthranilic acid (P = 0.007), anthranilic acid (P = 0.026), and L-tryptophan (P = 0.002). DISCUSSION: The study manifested that noninvasive taVNS effectively improved constipation and abdominal pain symptoms in patients with IBS-C. The alleviation of IBS-C symptoms may be attributed to the integrative effects of taVNS on rectal functions, mediated through vagal, cholinergic, and multiomics mechanisms.