Summary TRPV6 is specifically elevated in nasal epithelial cells of eCRSwNP. Blockade of TRPV6 reduces epithelial type 2 inflammation.

BACKGROUND:A pathological complete response (pCR) following neoadjuvant chemoradiation (CRT) is associated with a favorable prognosis in patients with locally advanced rectal cancer. Patients with metastatic colorectal cancer (mCRC) often receive systemic therapy, and some patients undergo primary tumor resection after preoperative therapy. However, whether oncological outcomes remain favorable in patients with mCRC and pCR in the primary tumor site (ypT0N0M1) following preoperative therapy is unknown. PATIENTS AND METHODS:Patients with mCRC who underwent preoperative therapy followed by primary tumor resection between March 2014 and August 2023, and in whom pCR was confirmed at the primary tumor site, were retrospectively included in this study. The outcome variables investigated were patient demographics, overall survival (OS), and progression-free survival (PFS). RESULTS:We included 57 patients who met the inclusion criteria. The median follow-up was 27.1 (range, 7.9-120.6) months. The 2-year PFS and 3-year OS rates in all the patients were 62.2% and 84.5%, respectively. Patients with a primary tumor site in the colon (n = 29) had superior OS (P = 0.039) and a trend toward superior PFS (P = .149) compared to those with a primary site in the rectum (n = 28). CONCLUSION:Patients with mCRC following preoperative therapy, particularly those with colon cancer, who experienced a pCR in the primary tumor site have a favorable prognosis.

3578 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and exhibit intrinsic resistance to immunotherapy. Emerging evidence suggests systemic therapy may enhance immunotherapy responsiveness, while radiotherapy could improve efficacy by overcoming resistance and reducing tumor burden. The MIRACLE-2 study evaluated the safety and efficacy of combining radiotherapy with systemic therapy and tislelizumab as first-line treatment for unresectable metastatic MSS rectal cancer (RC). Methods: MIRACLE-2 was a prospective, single-arm, phase II study. Inclusion criteria: MSS RC with primary tumor ≤10 cm from anal verge on MRI and synchronous unresectable metastases. Patients received hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or SBRT for metastases, followed by systemic therapy: FOLFOX-bevacizumab-tislelizumab for RAS/BRAF-mutant patients or FOLFIRI-cetuximab-tislelizumab for wild-type patients. Reassessment every 8 weeks. Patients achieving resectable disease underwent primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. Otherwise, systemic therapy continued until progression/intolerable toxicity. Primary endpoint: ETS rate (≥20% target lesion reduction at 8 weeks post systemic therapy initiation). Secondary endpoints: disease control rate (DCR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (38 males, 76.0%; median age 57 years, range 30-73). Among these, 52.0% had liver metastases, 8.0% lung metastases, and 40.0% both liver and lung metastases. RAS/BRAF mutations were detected in 56.0% of primary tumors. Median treatment courses: eight (range 3-12). Overall, 18% (9/50) attained no evidence of disease (NED). ETS rate: 76.0%; DCR: 88.0%. Median follow-up: 19.9 months (95% CI: 16.4-23.4). Among 34 patients with complete/partial response, median DOR: 8.0 months (95% CI: 5.2–10.8), with 1-year DOR rate of 20%. Median PFS: 9.3 months (95% CI: 7.1-11.5), with 1-year PFS rate of 33.4%. Median OS: 23.2 months (95% CI: 15.1-31.3), and 1-year OS rate: 93.3%. No grade 5 treatment-related adverse events (TRAEs) occurred. All-grade TRAEs: lymphopenia (95.9%), anemia (91.8%), and leukopenia (69.4%). Grade 3/4 TRAEs: lymphopenia (36.7%), neutropenia (26.5%), and leukopenia (20.4%). Conclusions: The combination of radiotherapy, systemic therapy, and tislelizumab showed a high ETS rate and manageable safety profile in first-line unresectable MSS RC. Long-term outcomes require further follow-up. Clinical trial information: NCT05359406 .

BACKGROUND:Current therapeutic outcomes for advanced colorectal cancer (CRC) remain suboptimal, and chemotherapy-based regimens continue to be the mainstay of treatment. Circular RNAs (circRNAs) can serve as templates for translating short peptides or proteins, and the resulting products actively regulate malignant tumour progression, making them attractive therapeutic targets. METHODS:We identified the novel protein PVT1-104aa translated from circPVT1, which is generated by back-splicing of the non-coding PVT1 gene. Its expression and clinical significance were examined in CRC clinical specimens and cell lines. Proliferation, metastasis, and tumour growth were assessed by CCK-8, colony formation, transwell, wound healing, and xenograft syngeneic tumour models. Mechanistic studies were performed by immunoprecipitation, ubiquitination assays, and protein half-life analysis. The relationship between PVT1-104aa, c-Myc, and PD-L1 was evaluated by promoter reporter assays, ChIP-qPCR, and immunohistochemistry. The therapeutic efficacy of combining PVT1-104aa inhibition with anti-PD-L1 therapy was tested in vivo. RESULTS:PVT1-104aa was significantly overexpressed in CRC and correlated with poor patient prognosis. Functionally, it drove tumour progression by promoting proliferation and metastasis. Mechanistically, PVT1-104aa enhanced c-Myc phosphorylation at Ser62, disrupted the c-Myc-FBW7 interaction, and thereby inhibited ubiquitin-mediated degradation of c-Myc, as shown by accelerated c-Myc turnover upon PVT1-104aa knockdown. In addition, PVT1-104aa regulated PD-L1 expression through c-Myc. Combining anti-PVT1-104aa with anti-PD-L1 therapy suppressed CRC growth and increased CD4+ and CD8+ T cell infiltration in xenograft syngeneic tumour models and CRC tissues. CONCLUSIONS:Our results uncover a pathogenic role of the PVT1-originated molecular species PVT1-104aa and suggest that targeting this pathway represents a promising therapeutic strategy for CRC treatment. KEY POINTS:Circ-PVT1 is upregulated in CRC patients and encoded a novel protein: PVT1-104aa. PVT1-104aa promotes CRC progression and predicts worse prognosis. PVT1-104aa enhance Myc expression through inhibition of Myc ubiquitination. PVT1-104aa regulate PD-L1 expression of CRC cells and modulate T cells infiltration in vivo.

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery and adjuvant chemotherapy is a standard therapy for locally advanced rectal cancer (LARC). However, a significant proportion of patients exhibit a poor response, and few studies focus on this subgroup's prognosis. The aim of this study was to investigate the prognosis of locally advanced rectal cancer patients with poor response to neoadjuvant chemoradiotherapy. Methods: Between July 2013 and August 2023, we retrospectively collected data from patients with LARC who received long-course nCRT and surgery at our hospital. Patients with tumor regression grade 3 were defined as poor responders, and their recurrence patterns, long-term oncological outcomes were analyzed. Results: A total of 135 patients were included in the analysis, with a median follow-up duration of 45 months. Recurrence occurred in 65 patients, with the following recurrence patterns: locoregional recurrence (n=12), lung metastasis (n=19), liver metastasis (n=8), metastases to other sites (n=3), multiple-site recurrence (n=13) and unknown site (n=10). The 5-year overall survival and 3-year disease-free survival were 56.8% and 53.1%, respectively. Despite poor response to nCRT, adjuvant chemotherapy emerged as an independent protective factor for overall survival [hazard ratio (HR) =0.415, 95% confidence interval (CI): 0.185-0.930, P=0.03]. Conclusions: Poor responders to nCRT in LARC have high risk of recurrence and metastasis, especially lung metastasis. Adjuvant chemotherapy could improve the overall survival in this group.

e15555 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and show low response to immunotherapy. Emerging evidence suggests combining radiotherapy with chemotherapy and PD-1 inhibitors may yield promising responses in locally advanced rectal cancer (RC). The MIRACLE-1 study evaluated this combination as upfront treatment for MSS RC with synchronous resectable metastases. Methods: MIRACLE-1 was a prospective, single-arm, phase II study. Inclusion criteria included MSS RC with primary tumor ≤10 cm from anal verge on MRI and limited liver/lung metastases deemed resectable. Patients received upfront radiotherapy: hypofractionated radiotherapy (HFRT) for primary lesion and HFRT or stereotactic body radiotherapy (SBRT) for metastases. Subsequently, six cycles of CAPOX plus Tislelizumab were administered. Tumor response was assessed after the third and sixth cycles. Further management included primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. For patients achieving no evidence of disease (NED), adjuvant Tislelizumab was continued for up to 1 year postoperatively. Other patients received investigator-determined subsequent therapy. Primary endpoint: 1-year NED rate. Secondary endpoints: objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (37 males, 74.0%; median age 60 years, range 28-71). Among these, 62.0% had liver metastases, 20.0% lung metastases, and 18.0% both liver and lung metastases. RAS/BRAF mutations were detected in 62.0% of primary tumors. Upon reassessment, 38 patients (76.0%) achieved partial response (PR), 10 (20.0%) stable disease (SD), and 2 (4.0%) progressive disease (PD). ORR was 76.0%. Additionally, 54% (27/50) attained NED. Median follow-up duration was 18.7 months (95% CI: 15.5-21.9). Median PFS was 17 months (95% CI: 8.7-25.3), and 1-year PFS rate was 61.2%. Median OS was not reached, with 1-year OS rate of 83.5%. One treatment-related death occurred due to immunotherapy-induced hepatitis. All-grade treatment-related adverse events (TRAEs): thrombocytopenia (93.8%), lymphopenia (81.3%), and anemia (77.1%). Grade 3/4 TRAEs: thrombocytopenia (39.6%), lymphopenia (14.6%), and neutropenia (12.5%). Conclusions: In MSS RC patients with synchronous resectable metastases, radiotherapy combined with CAPOX plus Tislelizumab demonstrated promising antitumor efficacy and manageable safety profile. While initial findings are encouraging, longer follow-up is needed to assess durable outcomes. Clinical trial information: NCT05359393 .

The incidence of early-onset colorectal cancer (EOCRC) is increasing worldwide, and CRC survivors may have an elevated risk of second primary cancer (SPC). This retrospective study analyzed 13,302 CRC patients diagnosed between 2008 and 2018 at a Chinese high-volume cancer center, including 635 (4.77%) who developed SPC after CRC. Patients were stratified by age at CRC diagnosis (<50, 50-69, and ≥70 years) to identify risk factors, cancer types, and prognostic significance of SPC. Multivariable Cox analysis showed that older age, neoadjuvant therapy, tumor location, T stage, N stage, M stage, and radiotherapy were independently associated with SPC in the overall cohort. Age-stratified analyses revealed heterogeneous associated factors, with radiotherapy being the only independent factor in the ≥70-year group. Five-year overall survival was comparable between the <50- and 50-69-year groups and was significantly better than in the ≥70-year group among all CRC patients and those with SPC. Early-stage patients with SPC had better overall survival than those without SPC, whereas advanced-stage patients without SPC had better survival. These findings suggest age-specific heterogeneity in SPC development and support tailored surveillance strategies after CRC.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disorder, characterized by persistent inflammation of the sinonasal mucosa and nasal polyp formation. The pivotal roles of interleukin (IL)-4/IL-13 signaling in CRSwNP pathogenesis is increasingly recognized, evidenced by the remarkable clinical success of biologics targeting this pathway. This review provides a concise overview of the IL-4/IL-13 pathway in CRSwNP, encompassing its molecular architecture, pathogenic mechanisms, current targeted therapies, and emerging therapeutic strategies.

The incidence of gastric cancer remains high and poses a serious threat to human health. Recent comprehensive investigations into amino acid metabolism and immune system components within the tumor microenvironment have elucidated the functional interactions between tumor cells, immune cells, and amino acid metabolism. This study reviews the characteristics of amino acid metabolism in gastric cancer, with a particular focus on the metabolism of methionine, cysteine, glutamic acid, serine, taurine, and other amino acids. It discusses the relationship between these metabolic processes, tumor development, and the body’s anti-tumor immunity, and analyzes the importance of targeting amino acid metabolism in gastric cancer for chemotherapy and immunotherapy.

e15524 Background: MSS tumors account for 95% of metastatic colorectal cancer and are characterized by a low response rate to immunotherapy. Emerging evidence showed that radiotherapy combined with chemotherapy and PD-1 inhibitors led to promising tumor responses in patients (pts) with locally advanced rectal cancer (LARC). MIRACLE-1 aims to investigate the safety and efficacy of such approach as upfront treatment of MSS LARC with resectable metastases. Methods: MIRALCE-1 was a prospective, single arm, phase 2 study. The main inclusion criteria include MSS LARC with a distance of ≤10 cm from the anus by MRI evaluation and a limited number of metastases in the liver and/or lungs that were eligible for curable resection. Eligible patients were treated with upfront radiotherapy including hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions. Afterwards, six cycles of systemic therapy consisted of CAPOX and Tislelizumab were administered. Then, reassessment was performed within 4 weeks afterwards by radiological and serological evaluations. Surgical resection, local ablative therapies or active surveillance was applied based on tumor response. For patients attained no-evidence of disease (NED), Tislelizumab was maintained until one year after surgery. Otherwise, the subsequent treatment was determined by the investigators. The primary endpoint is the 1-year NED rate. The secondary endpoints include objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicities. Results: From March 2023 to November 2024, 38 pts were enrolled and 20 were evaluable. At baseline, 60.0% of pts were male, median age was 57 years (range 34-71), 55.0% had liver metastases (mets), 15.0% had lung mets, and 30.0% had both liver and lung mets. 80.0% primary tumors had RAS/BRAF mutations. Upon reassessment, 18 (90.0%) pts had partial response (PR) and 2 (10.0%) had stable disease (SD). No patients showed progressive disease (PD). The ORR was 90.0%. 65% (13/20) pts attained NED. Median PFS and OS have not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were fatigue (85.0%), thrombocytopenia (65.0%), leukopenia (50.0%) and anemia (40.0%). The most frequent grade 3/4 TRAEs were thrombocytopenia (30.0%) and neutropenia (20.0%). Conclusions: Combination treatment of upfront radiotherapy, immunochemotherapy demonstrated a promising efficacy and a manageable safety profile in MSS LARC with resectable metastases. Translational study to identify predictive biomarkers is ongoing. Clinical trial information: NCT05359393 .

Cancer is a major global health challenge, urgently requiring innovative treatment strategies. Traditional chemotherapy regimens often lack adaptability to the dynamic tumor microenvironment. In recent years, artificial intelligence (AI) technologies, particularly reinforcement learning, have provided novel tools for optimizing personalized therapies. This study presents a novel AI-based framework utilizing the Proximal Policy Optimization (PPO) algorithm to simulate and optimize chemotherapy protocols within tumor models. The framework employs a system of dynamic differential equations to model the complex interactions among tumor cells, normal cells, and immune cells, with drug concentration serving as the primary control variable. By interacting with the tumor model environment, the PPO algorithm generates optimized drug administration strategies that simultaneously minimize tumor cell proliferation and mitigate drug-induced side effects. Experimental results demonstrate the efficacy of this approach in controlling tumor growth across both noise-free and noisy environmental conditions. Moreover, introducing noise into the training process notably improves the model's resilience and its ability to adapt to varying conditions.

Non-small cell lung cancer (NSCLC) is currently the most prevalent malignancy worldwide, and its therapeutic resistance poses an enormous challenge to current therapeutic efforts. As the most common internal modification of RNA molecules, n6-methyladenosine (m6A) affects RNA structure and function and regulates gene expression. It is widely acknowledged that this modification contributes to progression and resistance to drug therapy in NSCLC. Because tumors exhibit heterogeneous characteristics, the functional expression of m6A-modifying enzymes and the molecular mechanisms and downstream pathways they regulate exhibit distinct phenotypic characteristics. By precisely controlling the methylation process, understanding the specific regulatory mechanisms involved in m6A modification may result in more effective treatments for NSCLC progression and drug resistance. This review summarizes recent functional analyses of m6A modifications in NSCLC, focusing on their impact on therapeutic responses via modulation of specific gene expression levels. Furthermore, we examined the potential of m6A modifications as therapeutic interventions and predictive biomarkers for drug resistance, aiming to enable individualized and precise therapeutic strategies to treat NSCLC.

Background: A yield pathological T0 (ypT0) classification usually indicates the pathologically complete response of rectal cancer to neoadjuvant therapy. However, lymph node metastasis may still be present. Objectives: In this study, we aimed to evaluate the prognostic value of residual lymph node status in patients with pathological T0 rectal cancer after neoadjuvant therapy. Design: Retrospective cohort study. Methods: Patients with locally advanced rectal cancer (LARC) who had undergone preoperative therapy and were pathologically classified as having ypT0 disease at Fudan University Shanghai Cancer Center between December 2012 and September 2022 were retrospectively analyzed. Uni- and multivariate analyses were performed to evaluate the effect of the residual lymph node status on disease-free survival (DFS) and overall survival (OS). Results: A total of 457 patients had ypT0 disease; this included 413 patients with ypT0N0 and 44 with ypT0N1–2. Inadequate lymph node retrieval (<12, p = 0.002) and adenocarcinoma ( p = 0.009) were more common in the ypT0N0 group than in the ypT0N1–2 group. The ypT0N1–2 group showed marginal evidence of a higher probability of elevated pretreatment carcinoembryonic antigen levels and adjuvant chemotherapy than the ypT0N0 group ( p = 0.076 and p = 0.077, respectively). Patients with ypT0N0 had significantly better 5-year DFS than those with ypT0N1–2 (84.8% vs 68.4%, p = 0.016). However, no significant difference was observed in the 5-year OS between the two groups (93.9% vs 88.8%, p = 0.602). Multivariate analysis revealed that residual lymph node status was an independent prognostic factor for DFS (hazard ratio, 2.285; 95% confidence interval: 1.246–4.192, p = 0.008). Conclusion: Residual lymph node metastasis may affect DFS, but not OS, in pathological T0 patients who receive neoadjuvant therapy followed by radical surgery for LARC.

Background Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers.

T cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.

The data that support the findings of this study are openly available in ZENODO at https://doi.org/10.5281/zenodo.12722341.

Many biological processes related to cell function and fate begin with chromatin alterations, and many factors associated with the efficacy of immune checkpoint inhibitors (ICIs) are actually downstream events of chromatin alterations, such as genome changes, neoantigen production, and immune checkpoint expression. However, the influence of genes as chromatin regulators on the efficacy of ICIs remains elusive, especially in gastric cancer (GC). In this study, thirty out of 1593 genes regulating chromatin associated with a favorable prognosis were selected for GC. CHAF1A, a well-defined oncogene, was identified as the highest linkage hub gene. High CHAF1A expression were associated with microsatellite instability (MSI), high tumor mutation burden (TMB), high tumor neoantigen burden (TNB), high expressions of PD-L1 and immune effector genes, and live infiltration of immune cells. High CHAF1A expression indicated a favorable response and prognosis in immunotherapy of several cohorts, which was independent of MSI, TMB, TNB, PD-L1 expression, immune phenotype and transcriptome scoring, and improved patient selection based on these classic biomarkers. In vivo, CHAF1A knockdown alone inhibited tumor growth but it impaired the effect of an anti-PD-1 antibody by increasing the relative tumor proliferation rate and decreasing the survival benefit, potentially through the activation of TGF-β signaling. In conclusion, CHAF1A may be a novel biomarker for improving patient selection in immunotherapy.