Importance: Patients with pathological complete response (pCR) of rectal cancer following neoadjuvant treatment had better oncological outcomes. However, reliable methods for accurately predicting pCR remain limited. Objective: To evaluate whether transrectal ultrasound-guided tru-cut biopsy (TRUS-TCB) adds diagnostic value to conventional modalities for predicting pathological complete response in patients with rectal cancer after neoadjuvant treatment. Design, setting, and participants: This study evaluated data of patients with rectal cancer who were treated with neoadjuvant treatment and reassessed using TRUS-TCB and conventional modalities before surgery. This study is registered with ClinicalTrials.gov. Main outcomes and measures: The primary outcome was accuracy, along with secondary outcomes including sensitivity, specificity, negative predictive value, and positive predictive value in predicting tumour residues. Final surgical pathology was used as reference standard. Results: Between June 2021 and June 2022, a total of 74 patients were enroled, with 63 patients ultimately evaluated. Among them, 17 patients (28%) exhibited a complete pathological response. TRUS-TCB demonstrated an accuracy of 0.71 (95% CI, 0.58–0.82) in predicting tumour residues. The combined use of TRUS-TCB and conventional modalities significantly improved diagnostic accuracy compared to conventional modalities alone (0.75 vs. 0.59, P=0.02). Furthermore, TRUS-TCB correctly reclassified 52% of patients erroneously classified as having a complete clinical response by conventional methods. The occurrence of only one mild adverse event was observed. Conclusions and relevance: TRUS-TCB proves to be a safe and accessible tool for reevaluation with minimal complications. The incorporation of TRUS-TCB alongside conventional methods leads to enhanced diagnostic performance.

Colorectal cancer (CRC) is considered as an age-related disease, and cellular senescence (CS) plays a crucial role in cancer development and progression. Previous studies have shown the role of epigenetic changes in aging and cancer development, but the role of RNA pseudouridine (Ψ) modification in aging and cancer remains to be explored. Using bulk RNA sequencing, CRC cells with low Ψ writers expression levels have higher CS levels. We developed the Psi Score for assessing the transcriptomic profile of RNA Ψ modification regulation and found that the Psi Score correlates with CS. Furthermore, Psi-related senescence may be mediated by mTOR, TGF-β, TNF-α, and inflammatory response signaling pathways. Meanwhile, Psi Score could predict the anti-cancer treatment outcomes of anti-aging interventions and could be used to predict the response to immunotherapy. Overall, these findings reveal that RNA Ψ modification connected aging and cancer and provided novel insights into biomarker-guided cancer regimens.

Background: Neoadjuvant therapy followed by radical surgery is recommended for locally advanced rectal cancer (LARC). But radiotherapy can cause potential adverse effects. The therapeutic outcomes, postoperative survival and relapse rates between neoadjuvant chemotherapy (N-CT) and neoadjuvant chemoradiotherapy (N-CRT) patients have rarely been studied. Methods: From February 2012 to April 2015, patients with LARC who underwent N-CT or N-CRT followed by radical surgery at our center were included. Pathologic response, surgical outcomes, postoperative complications and survival outcomes (including overall survival [OS], disease-free survival [DFS], cancer-specific survival [CSS] and locoregional recurrence-free survival [LRFS]) were analyzed and compared. Concurrently, the Surveillance, Epidemiology, and End Results Program (SEER) database was used to compare OS in an external source. Results: A total of 256 patients were input into the propensity score-matching (PSM) analysis, and 104 pairs remained after PSM. After PSM, the baseline data were well matched and there was a significantly lower tumor regression grade (TRG) (P < 0.001), more postoperative complications (P = 0.009) (especially anastomotic fistula, P = 0.003) and a longer median hospital stay (P = 0.049) in the N-CRT group than in the N-CT group. No significant difference was observed in OS (P = 0.737), DFS (P = 0.580), CSS (P = 0.920) or LRFS (P = 0.086) between the N-CRT group and the N-CT group. In the SEER database, patients who received N-CT had similar OS in both TNM II (P = 0.315) and TNM III stages (P = 0.090) as those who received N-CRT. Conclusion: N-CT conferred similar survival benefits but caused fewer complications than N-CRT. Thus, it could be an alternative treatment of LARC.

Colorectal cancer is a highly heterogeneous malignancy characterized by complex interactions between tumor cells and the immune system. The tumor microenvironment (TME) plays a crucial role in colorectal cancer progression and response to therapy. However, the mechanisms regulating TME composition remain poorly understood because of the genetic and phenotypic diversity of tumor cells. In this study, we investigated the tumor-intrinsic factors contributing to TME formation and evaluated genotype-based combination strategies to enhance the efficacy of immunotherapy in colorectal cancer. Using RNA sequencing, single-cell analysis, and immunohistochemistry (IHC), we identified pro-oncogenic proteins associated with low immune activation. Functional studies using in vitro co-culture systems, subcutaneous colorectal tumor models, flow cytometry, and IHC revealed a role for CDC-like kinase 1 (CLK1) in tumor progression and immunosuppressive TME remodeling. Mechanistically, CLK1 activation led to hyperactivation of the Hippo signaling pathway, promoting nuclear translocation of Yes-associated protein (YAP) and subsequent transcriptional upregulation of the chemokine CXCL1. Elevated CLK1 expression correlated with increased infiltration of myeloid-derived suppressor cells (MDSC) and impaired antitumor immune responses. Knockdown (KD) of CLK1 significantly reduced MDSC recruitment and restored CD8+ T-cell activity. Moreover, combined CLK1 KD and anti–PD-1 therapy enhanced intratumoral CD8+ T-cell infiltration to a greater extent and elicited robust antitumor responses in murine colorectal cancer models. Collectively, our findings identify the CLK1–Hippo/YAP–CXCL1 signaling axis as a regulator of immune evasion and TME remodeling in colorectal cancer and highlight the potential of therapeutically targeting this axis to improve the efficacy of immune checkpoint blockade.

BACKGROUND: Locally advanced rectal cancer is a critical health concern, with neoadjuvant therapy emerging as a pivotal strategy to enhance survival rates. OBJECTIVE: This study aims to evaluate the prognostic value of achieving ypN0 status following neoadjuvant therapy patients with locally advanced rectal cancer, comparing survival outcomes among natural N0, downstaged N0, and ypN ⁺ groups. DESIGN: We conducted a post hoc analysis of the FOWARC trial, employing Kaplan-Meier survival analysis and Cox regression models to assess overall survival, disease-free survival, and locoregional recurrence-free survival. SETTINGS: The multicenter, randomized phase III FOWARC trial was conducted across 15 hospitals in China, adhering to ethical standards. PATIENTS: Our cohort included 449 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy followed by total mesorectal excision. INTERVENTIONS: Neoadjuvant chemoradiotherapy followed by total mesorectal excision. MAIN OUTCOME MEASURES: The primary endpoint was 5-year overall survival, with secondary endpoints being 3-year disease-free survival and 3-year locoregional recurrence-free survival. RESULTS: The 5-year overall survival for natural N0 and downstaged N0 groups were 88% and 89%, respectively, significantly higher than the 73% observed in the ypN⁺ group (p = 0.0034). The complete pathological response rate was markedly lower in the ypN⁺ group. Multivariable analysis showed the ypN stage as an independent prognostic factor for overall survival. LIMITATIONS: The study's retrospective design may introduce potential biases in patient selection and preoperative staging. CONCLUSIONS: Achieving ypN0 status via neoadjuvant chemoradiotherapy significantly improves survival in patients with locally advanced rectal cancer, regardless of ypT or cN status. This status not only serves as an independent prognostic factor, but may also help to guide hypothesis-driven, individualized postoperative-treatment strategies. See Video Abstract. ClinicalTrials.gov identifier: NCT01211210.

Cellular senescence, a fundamental hallmark of aging, plays a paradoxical, often pro‐tumorigenic role in cancer. This malignancy is largely driven by the senescence‐associated secretory phenotype (SASP), yet the mechanisms that govern the production of a pro‐tumorigenic SASP remain poorly understood. This study uncovers an epitranscriptomic axis in colorectal cancer (CRC) where the TRMT6/TRMT61A tRNA N ¹ ‐methyladenosine (m ¹ A) methyltransferase complex is aberrantly elevated, driving a senescent state in malignant cells. Mechanistically, TRMT6/61A‐dependent m ¹ A deposition on specific tRNAs enhances the translational efficiency of their cognate codons. This codon‐biased translational control selectively boosts the synthesis of ARG2. Accumulation of ARG2 subsequently activates mTOR and NF‐κB signaling and thereby establishes a robust SASP, which actively reprograms the tumor microenvironment by promoting the growth and invasiveness of neighboring cancer cells, activating cancer‐associated fibroblasts, and polarizing immunosuppressive M2 macrophages. Collectively, these findings define the TRMT6/61A‐ARG2 pathway as a driver for pro‐tumorigenic senescence in an m ¹ A‐dependent manner, revealing a new layer of translational control in aging‐associated pathology and offering a compelling rationale for developing senomorphic therapies.