Sen Zhang

Microsatellite-stable (MSS) colorectal cancer (CRC), comprising ~85–90% of cases, remains almost universally refractory to PD-1/PD-L1 monotherapy (objective response rate 5–10%), in stark contrast to the marked efficacy of immune checkpoint inhibitors (ICIs) in microsatellite-instability-high (MSI-H) disease. Here we synthesize evidence that CD8 ⁺ T cell exclusion, dysfunction, and exhaustion in MSS CRC are orchestrated not by cell-autonomous failures but by a multicellular immunosuppressive network in which tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) cooperate through mechanistically distinct yet spatially integrated axes. We propose a four-layer hierarchical model (physical exclusion, effector dysfunction, metabolic deprivation, and active suppression) that culminates in a stereotyped three-layer spatial niche best documented in CRC liver metastases (outer mCAF belt, Tex/TSTR band, inner SPP1 ⁺ TAM aggregates). MSS-associated mechanisms include the TAM-derived COX2/PGE2/TIGIT axis driving terminal exhaustion, a functional IL-10 ^- /IL-10 ⁺ Treg dichotomy, and CAF-mediated suppression of dendritic-cell CXCL9/10 production that blocks CXCR3 ⁺ CD8 recruitment. Effective therapeutic strategies must therefore target multiple layers simultaneously, including TAM reprogramming, stromal remodeling, precision Treg depletion, and MDSC differentiation, rather than relying on additional checkpoint inhibitors, which have proven insufficient as monotherapy or in dual combinations.

Colorectal cancer (CRC) remains a leading cause of cancer mortality with few effective targeted therapies. Kinesin family member 11 (KIF11), a motor protein essential for mitotic spindle assembly, is frequently overexpressed in multiple cancers. We hypothesized that nitidine chloride (NC), a natural benzophenanthridine alkaloid with documented anti-tumor activity, might suppress CRC by targeting KIF11.Molecular docking predicted a strong interaction between NC and KIF11 (− 9.0 kcal/mol). RNA sequencing, quantitative RT-PCR, and immunohistochemistry confirmed that NC treatment markedly downregulated KIF11 expression. Meta-analysis across public datasets showed consistent KIF11 mRNA overexpression in CRC (standardized mean difference [SMD] = 1.33; AUC = 0.87), while in-house immunohistochemistry on 416 clinical specimens demonstrated even stronger protein-level elevation (AUC = 0.99) that correlated with larger tumor size and deeper invasion. Single-cell RNA sequencing and spatial transcriptomics further revealed that KIF11 is preferentially expressed in proliferative malignant epithelial cells. Through CRISPR-based knockout screening and lentiviral silencing, KIF11 depletion impaired the growth or viability of the examined CRC cell models. Public ChIP-seq data suggested RAD21 occupancy near the KIF11 regulatory region, whereas reciprocal co-immunoprecipitation supported an association between the RAD21 and KIF11 proteins. Among genes co-expressed with KIF11,a pronounced enrichment was observed in pathways governing cell-cycle progression. Following KIF11 knockdown, transcriptomic profiling showed reduced expression across cell-cycle, DNA-replication, and chromatin-cohesion programs, alongside a reciprocal increase in amino-acid metabolism and stress-response genes. At the functional level, KIF11 depletion suppressed cell proliferation and induced G2/M-phase arrest. Taken together, these in vitro and limited xenograft data indicate that NC restrains CRC growth chiefly through the RAD21–KIF11 axis; KIF11 represents a promising preclinical target, though comprehensive systematic in vivo pharmacodynamic and translational animal validation remains absent in the current study and requires further independent investigation.

Colorectal cancer (CRC) imposes an escalating burden on global health systems. According to the GLOBOCAN 2022 statistics, CRC ranks as the third most frequently diagnosed malignancy and the second ...

Background: Patients with locally advanced microsatellite-stable/mismatch repair–proficient (MSS/pMMR) colorectal cancer show heterogeneous responses to neoadjuvant immunotherapy, and effective predictive biomarkers are lacking. Systemic nutritional status correlates with host immune function, but its predictive value for immunotherapy response in this population is unclear. This study aimed to explore the value of systemic nutritional indicators and their dynamic changes in predicting complete response (pCR) after neoadjuvant immunotherapy in these patients. Methods: Clinical data from 255 patients with locally advanced MSS/pMMR colorectal cancer who received neoadjuvant immunotherapy were retrospectively analyzed. Patients were randomly divided into a training cohort and a validation cohort at a ratio of 7:3. In the training cohort, univariate analysis was first performed to screen potential predictive variables, followed by multivariate logistic regression analysis to identify independent predictors of pCR and to construct a predictive model. The discriminative ability, calibration, and clinical utility of the model were evaluated using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. A nomogram was subsequently developed for visualized individualized prediction. Results: Multivariate analysis identified younger age (OR = 0.96, 95% CI: 0.93–0.99), lower post–neoadjuvant treatment carcinoembryonic antigen (CEA) levels (OR = 0.19, 95% CI: 0.05–0.70), and an increase in the Geriatric Nutritional Risk Index (GNRI) during treatment (OR = 1.07, 95% CI: 1.02–1.12) as independent predictors of achieving pCR. The logistic regression model incorporating these three variables demonstrated good predictive performance, with AUCs of 0.76 in the training cohort and 0.80 in the validation cohort. The model showed good calibration, and decision curve analysis indicated favorable net clinical benefit. The resulting nomogram provided a practical reference tool for individualized prediction of pCR probability. Conclusion: Age, post–neoadjuvant treatment CEA levels, and changes in the GNRI were independent predictors of pathological complete response following neoadjuvant immunotherapy in patients with locally advanced MSS/pMMR colorectal cancer. The predictive model and nomogram presented in this study provide a reference for clinical practice and provide a novel perspective for future studies combining nutritional interventions with immunotherapy.

Objective: Rectal cancer is a common malignant tumor, and the presence of distant metastasis is critically important for determining treatment strategies. This study aimed to develop a deep learning radiomics model based on contrast-enhanced transrectal ultrasound (CETRUS) imaging to predict distant metastasis in patients with rectal cancer. Methods: We retrospectively analyzed the clinical data and CETRUS imaging of 878 patients with rectal cancer treated at The First Affiliated Hospital of Guangxi Medical University. Univariate and multivariate logistic regression analyses were performed to identify relevant clinical variables. Deep learning radiomics features were extracted using a pretrained DenseNet201 model and subsequently selected via the Mann–Whitney U test, Spearman correlation analysis, and least absolute shrinkage and selection operator regression. Separate models were constructed based on clinical data, two-dimensional ultrasound (TDUS), color Doppler ultrasound (CDUS), and contrast-enhanced ultrasound (CEUS) imaging. The optimal deep learning radiomics model was then combined with the clinical model to develop an integrated predictive model. Results: The clinical prediction model achieved area under the curve (AUC) values of 0.631 and 0.604 in the training and test cohorts, respectively. Among the three deep learning radiomics models, the CEUS model demonstrated the best performance, with AUC of 0.950 and 0.740 in the training and test cohorts, respectively. The TDUS model achieved AUC of 0.935 and 0.586, while the CDUS model yielded AUC of 0.805 and 0.521. The integrated model combining the clinical and contrast-enhanced ultrasound radiomics models achieved AUC of 0.947 and 0.749 in the training and test cohorts, respectively. Conclusion: The clinical-deep learning radiomics model based on CETRUS showed promising predictive performance in assessing distant metastasis in rectal cancer patients. This approach has the potential to assist clinicians in developing personalized patient management strategies, pending further validation to confirm its clinical applicability.

Colorectal cancer (CRC) remains a significant global health challenge, characterized by high morbidity and mortality. Despite advances in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, many CRC cases exhibit treatment resistance and immune evasion, necessitating the identification of novel therapeutic targets. Follistatin-like protein 3 (FSTL3) has recently emerged as a key regulator in CRC progression, influencing immune suppression and therapy resistance. FSTL3 modulates the tumor microenvironment by promoting epithelial-mesenchymal transition (EMT), sustaining β-catenin signaling, and stabilizing c-Myc, which collectively enhance tumor invasiveness and metastatic potential. Additionally, FSTL3 contributes to immune evasion by upregulating immune checkpoint molecules such as programmed death-ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase 1 (IDO1), thereby suppressing cytotoxic T-cell activity. High FSTL3 expression correlates with poor prognosis and resistance to conventional chemotherapy, targeted agents, and immune checkpoint inhibitors. Given its pivotal role in CRC pathophysiology, FSTL3 represents a promising biomarker for disease prognosis and a potential therapeutic target. Future research should focus on developing FSTL3-targeted interventions, including monoclonal antibodies, small-molecule inhibitors, and combination strategies with immunotherapy. Understanding the precise molecular mechanisms underlying FSTL3-mediated tumor progression and immune escape will be essential for translating these insights into clinical applications.

Colorectal cancer is among the most common malignancies of the gastrointestinal tract. Immune checkpoint inhibitors (ICIs) have become a key component in the treatment of locally advanced rectal cancer (LARC), offering promising therapeutic outcomes. However, ICIs can occasionally cause significant adverse effects. Herein, we report a case of rectal cancer with suspected paraneoplastic myasthenia gravis (pMG) induced by immune checkpoint inhibitors (ICIs). Unfortunately, the patient lacked anti-acetylcholine receptor (AChR)/muscle-specific kinase (MuSK) antibody testing and muscle biopsy, which precluded a definitive diagnosis of pMG. Remarkably, following surgical resection, the patient not only achieved complete tumor eradication but also experienced full remission of myasthenia gravis (MG).

Expression patterns and underlying mechanisms of metabolism-related genes SMOX and SUCLG2 in pan-cancer remain unclear. We conducted a comprehensive pan-cancer analysis of SMOX and SUCLG2, to explore their potential roles and mechanisms of action. Comprehensive analysis of SMOX and SUCLG2 was performed through UCSC, TCGA, GEO, and other databases. We validated the expression levels, diagnostic value, and prognostic significance of SMOX and SUCLG2 in CRC using external databases and qPCR. Then, CCK-8 is used to detect proliferation of RKO and HCT116 after silencing or overexpressing of SUCLG2. The expression of SMOX was upregulated and that of SUCLG2 was downregulated in most cancers. Both SMOX and SUCLG2 exhibited significant correlations with cancer prognosis, tumor microenvironment, immune infiltration, stemness scores, tumor mutational burden, and microsatellite instability. The diagnostic and prognostic value of SMOX and SUCLG2 in CRC was confirmed through TCGA, GEO, and HPA, as well as qPCR. SUCLG2 overexpression inhibited the proliferation of RKO and HCT116, whereas SUCLG2 silence promoted their proliferation. Our data provide insights into the role of SMOX and SUCLG2 in pan-cancer, highlighting their association with prognosis, cancer immunity, and other cancer characteristics and also revealing their significance in cancer progression. SUCLG2 may inhibit the proliferation of CRC.

Objective: The purpose of this study is to identify and analyze the factors associated with achieving pathological complete response (pCR) in patients with locally advanced microsatellite stable (MSS) or proficient mismatch repair (pMMR) colorectal cancer who underwent neoadjuvant chemoimmunotherapy.Methods: A retrospective cohort study was conducted on 116 such patients at the First Affiliated Hospital of Guangxi Medical University from January 2023 to July 2024. Univariate and multivariate analyses were used to find factors associated with pCR. Perform Cohen’s Kappa coefficient analysis to assess the agreement between clinical staging and pathological staging following neoadjuvant chemoimmunotherapy.Results: Among 116 patients who received neoadjuvant chemoimmunotherapy followed by radical curative surgery, 32.8% (38/116) achieved a pCR. Univariate analysis showed that pCR was not associated with sex, tumor location, etc., (P > 0.05 for all), but was significantly associated with age, body mass index (BMI), neutrophil–lymphocyte ratio (NLR), systemic inflammation index (SII), albumin–to–globulin ratio (AGR), post–treatment carcinoembryonic antigen (CEA) levels, and natural killer (NK) cell count (P < 0.05). Multivariate analysis identified age (OR = 0.952, 95% CI: 0.911–0.995, P = 0.031) and sex (OR = 0.188, 95% CI: 0.057–0.625, P = 0.006) as independent predictors of pCR in locally advanced MSS or pMMR colorectal cancer. Kappa concordance tests indicated poor agreement between post–treatment clinical and pathological staging. The kappa value for clinical T staging versus pathological T staging was 0.006 (P = 0.823), and for clinical N staging versus pathological N staging was 0.187 (P < 0.001), with a concordance rate of 40.5% (47/116). Stratified by tumor location, in rectal cancer, clinical N staging had moderate agreement with pathological N staging (kappa = 0.273, P = 0.004, concordance rate 54.5%, 18/33), while in colon cancer, clinical T staging had negligible agreement (kappa = −0.006, P = 0.915), and clinical N staging had low concordance (kappa = 0.154, P = 0.001, concordance rate 36.1%, 30/83).Conclusion: Younger male patients demonstrated a significantly higher likelihood of achieving pCR following neoadjuvant chemoimmunotherapy. This study emphasizes the need to enhance the accuracy of clinical restaging after neoadjuvant chemoimmunotherapy.