The efficacy of postsurgical immunotherapy for gastric cancer (GC) remains controversial, and the effect of the number of dissected lymph nodes (DLNs) on the efficacy of immunotherapy remains unknown. We retrospectively reviewed 451 patients who received adjuvant or palliative therapies (including immunotherapy and chemotherapy) for GC at nationwide centers between 2020 and 2025 to investigate the influence of DLNs on postsurgical immunotherapy. Prognoses were assessed based on DLNs. In the adjuvant immunotherapy cohort (n = 139), the disease-free survival (DFS) was significantly lower in patients with DLNs >36 compared with those with DLNs ≤36 [hazard ratio (HR), 2.62; 95% confidence interval (CI), 1.39-4.95, P = 0.003)]. Moreover, patients with DLNs≤36 who received combined immunotherapy had a better DFS than patients who received only adjuvant chemotherapy (HR, 0.37; 95% CI, 0.17-0.78, P = 0.006). In the palliative immunotherapy cohort (n = 47), patients with DLNs>36 had significantly lower progression-free survival (PFS) (HR, 3.57; 95% CI, 1.61-7.94, P = 0.001) and DCR (6.67% vs 65.6%, P < 0.001) than those with DLNs≤36. Additionally, when matching with patients who received palliative immunotherapy without previous gastrectomy (DLNs = 0), the PFS decreased progressively in patients with DLNs = 0, DLNs>0 to ≤36, and DLNs>36 (median PFS, 16 vs. 11 vs. 3 months, P = 0.002). In conclusion, excessive lymph node dissection (DLNs≥36) compromised the efficacy of postsurgical adjuvant or palliative immunotherapy for GC.

The optimal surgical approach for reconstructing abdominal wall defects after radical resection of abdominal wall endometriosis (AWE) remains debated. This study aimed to compare the perioperative safety, recovery outcomes, and short-term efficacy of laparoscopy-assisted versus open repair for AWE surgery. In this single-center retrospective cohort study, 32 patients who underwent radical AWE resection and abdominal wall reconstruction between July 2023 and June 2025 were included. Patients were divided into two groups: open surgery (n = 18) and laparoscopy-assisted surgery (n = 14). Operative parameters, postoperative recovery, inflammatory markers, pain scores, and complications were compared between the two groups. The two groups were well balanced in baseline characteristics. The laparoscopy-assisted group had a significantly shorter incision length (6.46 ± 0.89 vs. 10.17 ± 1.60 cm, P < 0.001), fewer drainage tubes (0.79 ± 0.43 vs. 2.56 ± 0.51, P < 0.001), shorter drainage duration (2.79 ± 1.85 vs. 4.78 ± 2.60 days, P = 0.017), and shorter hospital stay (5.86 ± 1.83 vs. 7.61 ± 2.40 days, P = 0.026). Consistently, pain scores on postoperative days 3 and 5 were significantly lower in the laparoscopy-assisted group (P < 0.001). Notably, there was no significant differences in total operative time (P = 0.411), intraoperative blood loss (P = 0.453), postoperative specimen diameter (P = 0.876), time to first flatus (P = 0.320), time to first diet (P = 0.533), time to first ambulation (P = 0.443), and total complications (P = 1.000) between the two groups. No significant intergroup differences were found in incisional numbness or chronic pain at 6 months. Additionally, neither group exhibited abdominal hernia or recurrence of AWE. In conclusion, the laparoscopy-assisted approach offers a minimally invasive alternative that enhances early postoperative recovery—evidenced by shorter incisions, fewer drains, and less pain—while maintaining comparable operative times, safety profiles, and AWE radical treatment to the conventional technique.

Total laparoscopic distal gastrectomy with natural orifice specimen extraction (TLDG-NOSES) avoids the auxiliary incision needed in laparoscopic-assisted distal gastrectomy (LADG), potentially improving recovery. However, high-quality evidence on its safety and efficacy for distal gastric cancer surgery remains limited. Our study addresses this evidence gap by presenting the first multi-center, prospective, randomized controlled trial whether TLDG-NOSES improves postoperative recovery and reduces complications compared with LADG for distal gastric cancer. From April 2023 to January 2026, 232 patients with cT1-3N0-2M0 distal gastric adenocarcinoma were randomly assigned to TLDG-NOSES (n = 116) or LADG (n = 116). Operative time, blood loss, and lymph node yield were comparable between two groups (all P > 0.05). The overall complication rate was similar (6.9% vs. 8.6%; P = 0.624). Interestingly, TLDG-NOSES significantly shortened postoperative hospital stay (6.86 ± 2.82 vs. 8.38 ± 3.59 days; P < 0.001), accelerated first flatus (2.65 ± 1.39 vs. 3.39 ± 1.17 days; P<0.001) and liquid diet resumption (2.58 ± 0.97 vs. 3.69 ± 1.37 days; P < 0.001), and reduced pain on postoperative days 1-3 (all P < 0.05). Quality of life and cosmetic satisfaction were significantly better with TLDG-NOSES (both P < 0.001), while disease-free survival did not differ (P = 0.570), with no deaths in either group. TLDG-NOSES thus provides superior postoperative recovery, reduced pain, shorter hospital stay, and better quality of life without increasing complications, representing a safe and effective minimally invasive alternative for selected patients with distal gastric cancer, pending long-term oncological follow-up.

Background Pelvic floor dysfunction (PFD) is a common cause of chronic constipation which can reciprocally exacerbate pelvic floor burden. However, the characteristics and evolution of pelvic floor structures in patients with constipation remain unclear. This study investigates the characteristics and evolution of pelvic floor structures in constipated women aged over 40 years. Methods Clinical data were collected from female patients undergoing pelvic floor ultrasound at the Third Affiliated Hospital of Sun Yat-sen University from December 2020 to August 2023. Propensity score matching (PSM) minimized confounders between the constipation (n = 247) and non-constipation (n = 898) groups. We analyzed intergroup differences in ultrasound data and changes in pelvic floor structure over time among constipated patients. Results Significant intergroup differences emerged in uterine prolapse (P = 0.042), rectocele (P = 0.022), levator ani hiatus dilation (P=0.013), hiatus area (P < 0.01), the position of the uterus (P < 0.01), and rectal ampulla (P = 0.017) at maximal Valsalva maneuver (VM). Multivariate analysis identified rectocele (P = 0.023) and uterine descent at maximal VM (P = 0.026) as positively associated with constipation occurrence. Multiple ultrasonographic evaluations over two years revealed stable pelvic floor anatomy in non-constipated individuals but identified alterations in 78 constipated patients, including increased vesicocele (P = 0.039), uterine prolapse (P = 0.019), perineal hypermobility (P = 0.015), lower bladder (P < 0.001) and rectal ampulla (P < 0.01) positions at maximal VM, greater bladder descent (P < 0.01), and enlarged hiatus area (P < 0.01). Conclusion This study demonstrates that rectocele and uterine descent at maximal VM exhibit positive associations with constipation. Over time, further descent of the bladder, uterus, and rectum occurs in female patients with constipation, along with an increase in perineal mobility and levator ani hiatus area.

Background:Neuroblastoma is characterized by multiple immune evasion strategies, making it critical to explore the use of immunotherapy. CDK1 is known for its role in regulating cell cycle progression and is aberrantly expressed in various tumors, yet its role in NB and immunogenic cell death remains unclear. Methods:We investigated the association between the expression of CDK1 and the outcome of neuroblastoma according to the TCGA database and confirmed the results by tissue arrays. Furthermore, we evaluated the correlation between CDK1 expression and immune cell infiltration as well as cytokine effectiveness. Finally, in vitro and in vivo experiments were used to confirm the effects of a CDK1 inhibitor. Results:CDK1 was overexpressed in advanced neuroblastoma and was associated with poor prognosis. High CDK1 expression correlated with reduced immune cell infiltration and decreased levels of effector cytokines including IL-12, IFN-γ, and IRF1. Furthermore, the inhibition of CDK1 slowed the growth of neuroblastoma cells and promoted immunogenic cell death in neuroblastoma. CDK1 inhibition via RO-3306 suppressed tumor growth and induced hallmark features of ICD, including CRT exposure, HSP70 expression, and HMGB1 release. Conclusion:CDK1 inhibition not only slows neuroblastoma progression but also triggers DAMP release consistent with ICD and immune activation. CDK1 may be a potential prognostic marker and effective treatment target for improving immunotherapy efficacy in neuroblastoma patients.

Technique Conventional laparoscopic gastric resection requires an abdominal incision for specimen extraction, which not only affects cosmetic outcomes but also results in slower postoperative recovery. Therefore, we performed a total laparoscopic distal gastrectomy for gastric cancer with transvaginal natural orifice specimen extraction (GC-NOSES). This technique has been implemented at our center, and this study outlines the surgical procedure, accompanied by a video for a more comprehensive understanding. Results Strict adherence to the fundamentals of asepsis and oncological clearance was upheld during the operation. We smoothly performed a total laparoscopic distal gastrectomy for gastric cancer, with transvaginal specimen extraction, thus avoiding an abdominal incision. Postoperatively, the patient had negative surgical margins and was discharged without significant complications. Conclusion GC-NOSES removes the need for an abdominal incision for specimen extraction, which accelerates the recovery of the patient.

Massive abdominal wall defects resulting from radical abdominal wall endometriosis (AWE) resection present a major reconstructive challenge. This study aims to assess feasibility and short-term safety of a standardized retromuscular-onlay dual-mesh repair technique in this setting. In this single-center retrospective study, 9 patients with massive abdominal wall endometriosis underwent radical excision and standardized retromuscular-onlay dual-mesh reconstruction between January 2024 and June 2025. A series of postoperative complications was analyzed, including surgical site infection, symptomatic seroma, hematoma, wound pain and numbness, mesh infection, incisional hernia, and recurrence of abdominal wall endometriosis. All nine patients, with a history of cesarean delivery, were diagnosed with type III AWE. Clinical presentation uniformly featured a palpable abdominal wall mass and pain accompanying the menstrual cycle. Previous surgical intervention for AWE had been undertaken in 22.2

Preventing post-surgical recurrence and metastasis in advanced gastric cancer through tumor vaccines necessitates a more surgically compatible strategy. Here, we propose an intraoperatively applicable platform featuring a self-adjuvant tumor vaccine co-delivered with PD-1 blockade in fibrin gel (FG) to inhibit post-surgical tumor relapse. First, the tumor cell membrane vaccine is modified via simple insertion of DSPE-PEG-αCD40, which simultaneously endows the vaccine with targeting and self-adjuvant effects on antigen-presenting cells (APCs). This αCD40-modified vaccine (Vax-αCD40) significantly stimulates dendritic cell maturation and reprograms macrophages toward pro-inflammatory phenotypes in vitro and in vivo. Moreover, when Vax-αCD40 and αPD-1 are encapsulated within FG to form an adhesive “vaccine pool”, a positive feedback loop of CD40 expression-αCD40 stimulation on APCs exerts synergistic immune activation at the surgical site. In mouse models, this co-delivery system effectively suppresses local recurrence and peritoneal metastasis, which is associated with increased APC infiltration, cytotoxic CD8+ T cell expansion, and durable immune memory. This strategy represents a translatable approach for preventing recurrence in gastrointestinal malignancies.

Introduction:Oxaliplatin (OXA) and 5-fluorouracil (5-Fu) are standard chemotherapy agents used to treat advanced gastric cancer (GC). However, their clinical efficacy is often limited by systemic toxicity, poor tumor selectivity, and suboptimal therapeutic outcomes when administered as monotherapy. These limitations underscore the need for innovative approaches to improve chemotherapy sensitivity and treatment efficacy. Methods:We developed a glucose-responsive, RGD peptide-functionalized biporous silica nanocarrier (R-BSN). This system integrates hollow glucose oxidase (hGOx)-modified micelles onto hollow mesoporous silica nanoparticles functionalized with RGD peptides, enabling targeted, sustained drug release and inducing a starvation effect in tumor cells. Results:The glucose-triggered biporous release strategy significantly prolongs the drug release profile, ensuring sustained chemotherapy delivery while simultaneously depleting intratumoral glucose to enhance therapeutic efficacy. This strategy not only increases chemotherapy potency but also exacerbates oxidative stress in tumor cells, leading to the induction of immunogenic cell death (ICD). Furthermore, R-BSN exhibits robust anti-tumor activity in both subcutaneous tumor models and peritoneal metastasis models, supporting its potential for multi-pathway tumor eradication. Conclusion:The glucose-triggered biporous silica nanocarrier offers a promising strategy to enhance chemotherapy outcomes in advanced gastric cancer, integrating sustained drug release, starvation therapy, and amplification of oxidative stress. This approach holds significant potential for clinical translation in gastric cancer treatment.

INTRODUCTION AND IMPORTANCE:Spigelian hernia, a rare primary abdominal wall defect accounting for 2 % of all hernias, poses diagnostic challenges due to its anatomical proximity to the semilunar line. Its coexistence with inguinal hernia further complicates management. This report introduces an innovative laparoscopic approach for concurrent Spigelian-inguinal hernia repair. CASE PRESENTATION:A patient presented with left lower abdominal and inguinal pain. CT revealed a 4-cm Spigelian hernia ring. We performed the modified TAPE technique combining TAPP and IPOM principles: The hernia sac was reduced transabdominally, followed by preperitoneal mesh placement with peritoneal flap closure. Postoperative recovery was uneventful, with discharge on day 3. Three-month follow-up confirmed durable repair without complications. CLINICAL DISCUSSION:Spigelian hernia carries higher incarceration risks due to narrow fascial defects. While imaging advances improve detection rates, 30-50 % are initially misdiagnosed. Our modified TAPE technique addresses dual challenges: 1) Preperitoneal mesh placement avoids visceral contact seen in IPOM; 2) Peritoneal flap closure prevents mesh migration. Comparative studies show laparoscopic approaches reduce recurrence rates (1.2 % vs 4.7 % open) with shorter hospital stays. CONCLUSION:This case validates the modified TAPE technique as a safe, effective solution for Spigelian-inguinal hernia complex. The hybrid approach leverages laparoscopic advantages while mitigating traditional limitations, demonstrating 100 % early success in our series. This strategy warrants broader application in specialized hernia centers.

CD155 is a crucial factor in the regulation of T cell function and contributes to immune escape. CD155 upregulation has been found in several types of cancer. However, the mechanism by which CD155 regulates CD8+ T cell function in colorectal cancer remains unclear. Here we investigated the role and mechanism of CD155 in the regulation of CD8+ T cell function. We studied the expression of CD155 in colorectal cancer tissues through western blot, immunohistochemistry, and the TCGA database. We verified the effects of CD155 on the functions of colorectal cancer cells and CD8+ T cells through in vitro experiments. We demonstrated that CD155 affects CD8+ T cell migration and thus promotes tumor growth in a mouse subcutaneous tumor model. We then tested the changes in the PI3K/AKT/NF-κB pathway in CD8+ T cells by flow cytometry. We demonstrated that stable CD155 expression was negatively correlated with prognosis in colorectal cancer patients. In vitro experiments confirmed that CD155 does not affect tumor cell proliferation, migration, or invasion. We also revealed that CD155 downregulated the function and migration of CD8+ T cells in vivo and in vitro. Furthermore, CD155 might regulate CD8+ T cells function via the PI3K/AKT/NF-κB pathway. This study revealed that CD155 can promote the progression of colorectal cancer by regulating the PI3K / AKT-NF-κB pathway to promote the depletion of CD8+ T cells and reduce their migration to the tumor microenvironment. CD155 may become an important prognostic biomarker and an effective target for colorectal cancer immunotherapy.

Background Patients with colon cancer liver metastases (CCLM) frequently exhibit poor responses to immunotherapy, a phenomenon attributed in part to an immune desert tumor microenvironment. This study aimed to comprehensively characterize the immune landscape in primary colon cancers and their matched liver metastases via single-cell transcriptome analysis, with the goal of identifying potential immunotherapeutic targets.Methods Tumor specimens from patients with CCLM were subjected to single-cell RNA sequencing. Immune subpopulations were profiled with emphasis on exhausted T cells (Tex)—including both CD8+ and CD4+ ANK3+ subsets—as well as on a distinct stress response T-cell subset (TSTR) defined by high HSPA1A/HSPA1B expression. In parallel, we performed assessments of the phenotype and prognostic impact of SPP1high myeloid cells, along with in vitro assays to examine their role in modulating T-cell number and function.Results Liver metastatic lesions exhibited a significantly elevated infiltration of Tex compared with primary tumors. Notably, Tex cells exhibited upregulated expression of exhaustion-related marker genes such as ANK3, ZBTB20, ETV6, and CAMK4, which were markedly downregulated in TSTR cells. TSTR was identified as an intermediate developmental state between effector and exhausted T cells in patients with CCLM, suggesting that TSTR cells represent a distinct state from exhausted T cells. Furthermore, myeloid cells expressing high levels of secreted phosphoprotein 1 (SPP1), along with apolipoprotein C-I and apolipoprotein E, were associated with poor prognosis in patients with CCLM. In vitro studies revealed that Macro_SPP1high cells diminished T-cell populations and triggered a stress response state in both CD4+ and CD8+ T cells via the SPP1/CD44/PI3K/AKT signaling pathway in a CD44-dependent manner. Importantly, combination treatment with anti-SPP1 and anti-programmed cell death protein-1 antibodies significantly inhibited liver metastasis growth, enhanced dendritic cell maturation, decreased M2-polarized macrophages, and restored T-cell infiltration and function.Conclusions These findings reveal a previously unrecognized relationship between Macro_SPP1high cells and HSPA1Ahigh/HSPA1Bhigh T cells in driving CCLM progression, suggesting a potential synergistic therapeutic approach that could boost immune checkpoint treatment efficacy in patients with CCLM.

BACKGROUND:Immunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC. METHODS:Histone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments. RESULTS:In the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death-associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8+ T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC. CONCLUSION:The combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials.

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune checkpoint blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-β receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing immunostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response. Moreover, NCG responded to the acidic microenvironment and released Gal, inhibiting phosphorylation and inducing immunosuppressive Smad2/3 signaling. Consequently, the differentiation of MDSCs was inhibited, M1-like polarization of tumor-associated macrophages was induced, and the immunosuppressive barrier of tumor-associated fibroblasts was destroyed to increase the infiltration of effector T cells, which reversed the immunosuppression of the tumor microenvironment and improved the therapeutic efficacy of anti-PD-L1 antibodies. Notably, in the liver metastasis mouse model, combination therapy using NCG (+) and aPD-L1 inhibited the growth of colon cancer liver metastasis, manifesting potential in treating this popular yet intractable malignancy. STATEMENT OF SIGNIFICANCE: Only a limited number of patients with colorectal cancer and liver metastasis can benefit from immune checkpoint blockade therapy, as most of them are microsatellite stable, immunologically cold tumors. Interestingly, there is compelling evidence that sonodynamic therapy (SDT) can convert immunosuppressed cold tumors into hot ones, trigger tumor immunogenic cell death non-invasively, and boost cytotoxic T cells infiltration. However, its therapeutic efficacy is constrained by the abundance of transforming growth factor-β (TGF-β) cytokines in the tumor microenvironment. Here, we reported a TGF-β-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosuppressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy.

Abstract Neurogenic erectile dysfunction (nED) is one of the most common and intractable postoperative complications of rectal and prostate cancer surgery and sometimes accompanies patients lifelong. The transplantation of stem cells has been proved a promising way for treatment. However, the therapeutic efficacy is severely impaired by excessive cell loss and death and poor accumulation in the injury site along with the traditional implantation strategy. Herein, an EPO‐loaded multifunctional hydrogel was designed. The hydrogels' adhesive property and mechanical strength were enhanced by adding catechol‐catechol adducts, thus significantly improving adipose‐derived stem cells (ADSC) retention and rescuing cell loss in the injury site. Meanwhile, the sustained release of EPO effectively ameliorated the viability and paracrine activity of ADSC, leading to enhanced migration of Schwann cells and differentiation of PC12 cells in vivo. On a bilateral cavernous nerve injury rat model, the present stem cell‐EPO‐hydrogel implanted strategy could significantly alleviate erectile dysfunction. The higher expression of Tuj1 and lower expression of GFAP in the major pelvic ganglia (MPG) indicated the acceleration of neural differentiation while the suppressing development of astrocytes. Also, the combined therapy restored the expression levels of eNOs, nNOs, and α‐SMA in penile tissues, suggesting the rehabilitation of the penis. Further analysis of Masson trichrome staining and apoptosis evaluation of the corpus cavernosum showed the preservation of vascular endothelium content and the prevention of penile fibrosis after denervation. Overall, we believe that this combined strategy presents a promising way not only for restoring neurogenic erectile function but also for the clinical translation of stem cell therapy.

Background Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression. Methods CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages. Results CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155+ TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155+ macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155–⁄– bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155+ TAMs. Conclusions These findings indicated that CD155+ TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155+ TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.

Background: Preoperative evaluation of the T stage and prognosis of colorectal cancer (CRC) is vital for patients' management. Some of the known limitations of conventional computed tomography (CT) in the diagnosis of CRC needs to be resolved. Therefore, a deep learning system was developed by using patients' preoperative CT images to classify T stage and predict prognosis of CRC. Methods: Resnet50 (R), Inception-V3 (I), and Efficientnet-B5 (E) were adopted as the base model, and the three base model accepted CT images as multi-model image inputs and the output probabilities of the three networks were averaged to form an colorectal cancer ensemble model (CRCEM). This deep learning system was developed based on preoperative CT images of 654 patients (training cohort, n=393; validation cohort, n=131; test cohort, n=130). The performance of classifying T stage was assessed by our model, such as CRCEM (T1-2, T3, T4), CRCEM (T1-2, T3-4), and CRCEM (T1-3, T4). Then an observed study was conducted to evaluate our scheme performance in classifying T stage with two experienced radiologists. Furthermore, the output images of T stage were used as input and determined whether the tumor in the input CT images had a good or poor prognosis by using selected 284 patients (training cohort, n=228; test cohort, n=56), and this model was named as CRCEM (prognosis). Findings: Area under the curve (AUC) of classifying T stage in CRCEM (T1-2, T3, T4), CECEM (T1-2, T3-4), and CRCEM (T1-3, T4) was 0.859, 0.925, and 0.958, respectively. The AUC of classifying T1-2 vs. T3-4 was 0.749 and 0.763 in radiologist 1 and radiologist 2, respectively, and the AUC of classifying T1-3 vs. T4 was 0.774 and 0.765 in radiologist 1 and radiologist 2, respectively. Kappa value for inter-radiologist agreement was 0.792, (P<0.001). Meanwhile, AUC in classifying prognosis of CRC was 0.872. Interpretation: This study suggested that an effective method for classifying T stage and prognosis had been developed based on preoperative CT images, and held great potential for precise treatment of CRC. Funding: The project described was supported in part by the Science and Technology Planning Project of Guangdong Province (2019B030316011 to Hongbo Wei, 2021A0505030020 and 2017B020227009 to Bo Wei), and the Guangdong Provincial Key Laboratory of Digestive Cancer Research (2021B1212040006).Declaration of Interest: The authors declare no potential conflicts of interest.Ethical Approval: This study was approved by Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University.

Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced­ stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immunomodulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcutaneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Mechanistically, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1- and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π -conjugated polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.

TIGIT is a lymphocyte surface receptor, which is mainly expressed on the surface of CD8+T cells. The role of TIGIT in colorectal cancer and its expression pattern in colorectal cancer infiltrating lymphocytes are still controversial. This study aimed at identifying the function of TIGIT in colorectal cancer. Patients with colorectal cancer showed significantly higher TIGIT+CD8+T cell infiltration in tumor tissues, metastases compared with paired PBMC and normal tissues through flow cytometry. TIGIT+CD8+T cells showed an exhausted phenotype and expressed low levels of killer cytokines IFN-γ, IL-2, TNF-α. In addition, more inhibitory receptors such as PD-1, LAG-3, and TIM-3 were expressed on the surface of TIGIT+CD8+T cells. TGF-β1 could promote the expression of TIGIT and inhibit CD8+T cell function in vitro. Moreover, the accumulation of TIGIT+T cells in tumors was associated with advanced disease, predicted early recurrence, and reduced survival rates in colorectal cancer patients. Our results indicate that TIGIT can be a biological marker for the prognosis of colorectal cancer, and TIGIT can be used as a potential target for treatment.