This updated analysis of the STELLAR trial reports 5-year outcomes comparing short-course radiotherapy followed by chemotherapy (SCRT-based total neoadjuvant therapy [TNT]) with standard long-course chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients with distal or middle-third LARC were randomly assigned to receive either SCRT-based TNT or CRT. At a median follow-up of 68.7 months, the 5-year disease-free survival (DFS) was 62.0% in the TNT group and 58.7% in the CRT group, with a hazard ratio (HR) for DFS of 0.849 (95% CI, 0.662 to 1.089). Five-year overall survival (OS) was significantly higher with TNT (78.1% v 69.7%; HR, 0.739 [95% CI, 0.550 to 0.993]). Distant metastasis (DM) and locoregional recurrence (LRR) rates were similar between the two groups. In high-risk patients (per European Society for Medical Oncology criteria), TNT was associated with improved OS (HR, 0.663 [95% CI, 0.469 to 0.937]) and showed a nonsignificant trend toward improved DFS (HR, 0.765 [95% CI, 0.568 to 1.032]). In patients with DM or LRR, TNT was associated with both improved postrecurrence progression-free survival (HR, 0.691 [95% CI, 0.497 to 0.961]) and postrecurrence survival (HR, 0.698 [95% CI, 0.490 to 0.994]). These results suggest that SCRT-based TNT provides a durable survival advantage and is a viable alternative to CRT, especially in patients with high-risk disease.

ABSTRACT Background Colorectal cancer (CRC) is one of the most commonly occurring cancers all over the world. Because of the high metastasis rate, the 5‐year survival rate of metastatic CRC is only around 10%. CRC cells trigger the remodeling of the tumor microenvironment (TME), so decoding the TME between metastatic and primary sites becomes crucial. Methods Single‐cell sequencing and analysis were performed on 36 samples from four anatomical locations in nine untreated CRC liver metastasis patients. Cells from primary and metastatic sites were compared, and TMEs were validated. Genes from primary and metastatic sites were compared using a nonparametric test. Results Eleven major cell types were identified, and high heterogeneity of cell distribution among different locations was observed. We revealed several new features in liver metastatic tumors, including CXCL13 + CD4 T cells and regulatory CD4 T cells enriched, exhausted CD8 + T cells (Tex) increased, SPP1+ tumor macrophage increased, IGFBP7+ cancer‐associated fibroblasts in the metastatic TME, and the relative activation of the linoleic acid metabolism pathway. Besides, tumor cells contributed to four distinct biological modules, encompassing apoptosis, epithelial‐mesenchymal transition, the cell cycle, and immune processes. Conclusion Our study contributes new features for the microenvironment of colon cancer and liver metastasis, which may provide unique insights for novel biomarkers and potential treatment strategies.

Chemoradiotherapy is the principal approach for treating a wide range of human cancers. However, its therapeutic outcomes in clinical settings are frequently impaired by resistance to tumor chemoradiotherapy. In this study, we demonstrated that kinesin family member 26A (KIF26A) is downregulated in chemoradioresistant colorectal cancers, as revealed by transcriptomic analyses of colorectal cancer tissues and cell lines. Reduced KIF26A levels predicted diminished responsiveness to chemoradiotherapy and unfavorable outcomes in patients with colorectal cancer. Furthermore, lower KIF26A expression was associated with colorectal cancer (CRC) progression, migration, and invasion. This is the first demonstration that KIF26A interacts with Ku70 to suppress the formation of the DNA-dependent protein kinase (DNA-PK) complex, thereby preventing activation of non-homologous end joining (NHEJ) for repairing DNA damage. This makes cancer cells more vulnerable to DNA damage from chemoradiotherapy, thereby enhancing their sensitivity. To address chemoradio-resistance in KIF26A-low-expressing cells, we ascertained that histone deacetylase inhibitors (HDACi) could enhance acetylation of the KIF26A promoter, upregulate KIF26A, and boost the sensitivity of chemoradiotherapy-resistant cells. Thus, our research elucidates the function of KIF26A in the NHEJ repair process and indicates that combining HDACi with chemoradiotherapy may serve as a promising therapeutic modality for colorectal cancer.

Objective: Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment. We previously reported that high murine double minute 1 (MDM1) expression in patients with rectal cancer is linked to a favorable chemoradiation response. In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer (CRC) patients was evaluated. Methods: Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation. RNA sequencing revealed that MDM1 regulates tumor protein 53 (TP53) expression and apoptosis. A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression. The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated. Results: Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker. The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression. MDM1 affected p53 expression, thereby regulating apoptosis. MDM1 overexpression limited YBX1 binding to TP53 promoter, regulated TP53 expression, and rendered CRC cells more sensitive to chemoradiation. In CRC cells with low MDM1 expression, a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy. Conclusions: The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways, which is the basis for the underlying molecular mechanism, and serves as a possible predictive marker for chemoradiotherapy prognosis.

BACKGROUND:Metastases in the lateral pelvic lymph nodes or mesenteric lymph nodes represent distinct categories of mid-low rectal cancer. This study investigated the patterns of mesenteric and lateral pelvic lymph node metastases in mid-low rectal cancer; the survival benefit of postoperative treatment was also analysed in these groups. METHODS:This retrospective multicentre study included consecutive patients with mid-low rectal cancer who underwent total mesorectal excision with lateral pelvic lymph node dissection in three Chinese institutions between 2012 and 2020. The primary outcome was metastatic patterns and clinicopathological features of patients with mesenteric lymph node and lateral pelvic lymph node involvement. The secondary outcome was survival. RESULTS:Of 566 patients treated during the study period, 407 were selected. Four lymph node metastasis patterns were compared: metastasis to both mesenteric and lateral pelvic lymph nodes (68 patients, 17%), metastasis confined to lateral pelvic lymph nodes (24 patients, 6%), metastasis confined to mesenteric lymph nodes (121 patients, 29.7%), and neither mesenteric nor lateral pelvic lymph node metastasis (194 patients, 47.7%). Patients with metastases confined to lateral pelvic nodes had a lower proportion of poor histological types (P = 0.003), lymphatic invasion (P = 0.001), and number of lateral pelvic nodal metastases (P = 0.005) compared with patients with both mesenteric and lateral pelvic lymph node metastases. Independent of preoperative treatment, metastasis confined to the lateral pelvic nodes was associated with a significantly better prognosis than metastasis in both the mesenteric and lateral pelvic lymph nodes (3-year overall survival: 78.6 versus 47.2%, P = 0.007; 3-year disease-free survival: 65.7 versus 24.9%, P = 0.011), and it was similar to that of patients with metastasis confined to the mesenteric nodes (3-year overall survival: 78.6 versus 85.4%, P = 0.559; 3-year disease-free survival: 65.7 versus 70.4%, P = 0.447). CONCLUSION:Patients with metastasis confined to lateral pelvic lymph nodes have comparable pathological features and prognoses to those with metastasis confined to mesenteric nodes; such disease can be managed and treated in the same way as regional lymph node metastasis.

BACKGROUND:To evaluate the efficacy and toxicity of combining neoadjuvant immune checkpoint inhibitors (ICIs) with chemoradiotherapy (CRT) for patients with mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC). METHODS:PubMed, Embase, Cochrane Library, and Medline databases were searched. Phase I-III clinical trials reporting pathologic complete response (pCR) or overall CR (pCR + clinical CR) rates for neoadjuvant ICIs plus CRT in pMMR LARC were included. Studies that only enrolled patients with mismatch repair-deficient LARC were excluded. Data were analyzed at trial and arm levels and pooled using random-effects models. Primary outcomes were pCR and overall CR rates. Toxicity occurrence was also measured. RESULTS:In total, 19 trials (n = 1324) were included. At trial level, pooled odds ratios (95 % CIs) of overall CR and pCR rates for neoadjuvant ICIs plus CRT were 1.72 (1.21-2.44) and 1.68 (1.08-2.62), respectively. At arm level, compared with CRT, neoadjuvant ICIs plus CRT significantly improved overall CR (42 % vs 24 %, P < 0.001) and pCR rates (37 % vs 24 %, P = 0.008). Compared with ICIs plus long-course CRT, chemoimmunotherapy plus short-course radiotherapy significantly increased overall CR (51 % vs 36 %) and pCR (48 % vs 30 %) rates (both P < 0.001). Pooled incidence of grade 1-2 and ≥ 3 treatment-related adverse events was 63 % and 28 %, respectively-similar to CRT alone. CONCLUSION:Neoadjuvant immunotherapy plus CRT is a promising treatment strategy for pMMR LARC, with improved CR rates and manageable toxicity. Chemoimmunotherapy plus short-course radiotherapy exhibits superior efficacy. Further investigation on long-term outcomes and optimal combined regimens is warranted.

Despite the critical role of tumor-draining lymph nodes (TDLNs) in immunity, their heterogeneity is poorly understood. We employ single-cell and bulk RNA sequencing (RNA-seq) to dissect the immune landscape of TDLNs in colorectal cancer (CRC) cohorts. We reveal that enlarged TDLNs (L-TDLNs) are enriched with CD8+ effector T (Teff) cells exhibiting a distinct metallothionein (MT)-positive signature. CD8+MT+ Teff cells exhibit heightened cytotoxicity and a stress-adapted phenotype, which are critical mediators of anti-tumor immunity. CD8+MT+ Teff cells originate from L-TDLNs, where they undergo specific differentiation, and subsequently migrate to tumor. Moreover, patients with a high level of CD8+MT+ Teff cells in tumor show a significant survival advantage, in particular those treated with adjuvant chemotherapy. These findings highlight the importance of L-TDLNs in shaping effective anti-tumor immune responses, proposing the CD8+MT+ Teff cells as a prognostic biomarker and potential therapeutic target in CRC.

OBJECTIVES:To compare the value of tumor stroma ratio (TSR) and radiomic signature from baseline MRI for stratifying the risk of distant metastases (DM) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS:Data from 302 patients with LARC who underwent neoadjuvant chemoradiotherapy and total mesorectal excision in our hospital between 2015 and 2018 were retrospectively reviewed, and the patients were randomly allocated into the training and validation cohorts in a ratio of 7:3. Patients were followed-up for more than 3 years postoperatively with metachronous DM as the endpoint. Independent risk factors for DM-free survival (DMFS) were analyzed using Cox regression. The TSR of endoscopic biopsy specimens was scored automatically. Totally 1229 radiomic features of each tumor were extracted from baseline MRI, and the Radscore was calculated. RESULTS:The median follow-up time was 54.3 (51.6-57.1) months, and the 3-year DMFS was 83.8%. The best cutoff value of the TSR to distinguish a patient's DM risk was 0.477 (Sen=70.8%, Sep=78%, P <0.001). Increased TSR (HR=3.072, P =0.006) and Radscore (HR=719.231, P =0.023), advanced MR-evaluated T stage (HR=2.660, P =0.023) and ypN (HR=2.362, P =0.028) stage were independent risk factors for DMFS. The area under the curve of the combined model was significantly higher than that of the radiomic model ( P =0.013) but without a significant advantage over the TSR model ( P =0.086). CONCLUSION:TSR of colonoscopic biopsies can independently stratify DM risk in patients with LARC. The TSR model is the most convenient and efficient method for DM risk stratification in LARC.

The National Health Commission of the People's Republic of China Guidelines for Diagnosis and Treatment of Colorectal Cancer (2025 edition), based on evidence-based medicine, integrates cutting-edge international advances with Chinese clinical practice, and supplements and completes the previous versions. This version of the guidelines, retains the core diagnostic and treatment framework, highlights new contents such as "Surgical treatment of anal canal cancer" and "New technologies and advances in diagnosis and treatment", and systematically summarizes the core points in the surgical treatment, medical oncology treatment, radiation oncology treatment, imaging, and pathology treatment. It is designed to help clinicians quickly grasp the key points of the guidelines and promote the standardization, precision, and consistence of colorectal cancer diagnosis and treatment.

Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies.

Purpose: The purpose of this study was to assess the prognostic significance of the modified diagnostic biopsy-adapted immunoscore (mIS(b)) in determining the outcomes for patients with locally advanced rectal cancer (LARC) in a neoadjuvant setting. Methods and Materials: We included 181 patients with LARC from a single subcenter of a prospective study comparing total neoadjuvant therapy (TNT) based on short-course radiation therapy with long-term chemoradiation therapy (CRT). Tumor biopsies at baseline were stained for CD8+ and CD3+ T-cell densities. The mIS(b) was developed using mean percentile of CD8+ T-cell density and CD8/CD3 ratio. Patients were classified into low (0%-25%), intermediate (>25%-70%), and high (>70%-100%) in both groups. The relativity among different lymphocytes and their correlation with survival were illustrated. Survival analyses and Cox regression models were used to compare the prognostic values of mIS(b) and diagnostic biopsy immunoscore for survival outcomes and to assess the role of mIS(b) in TNT and CRT subgroups, respectively. Results: In this study, 151 (83.4%) patients received surgery, and 30 (16.6%) followed a watch and wait strategy. A strong correlation was found between CD8+ and CD3+ T-cell densities (R = 0.86; P < .001), whereas a weak correlation was witnessed between CD8+ and CD8/CD3 ratio (R = 0.45). The 3-year disease-free survival for the entire cohort was 69.9%, with 57.2%, 68.6%, and 85.5% for the low, intermediate, and high mIS(b) groups, respectively (P = .01), whereas diagnostic biopsy immunoscore failed to distinguish survival outcomes. Multivariate analysis revealed mIS(b) to be an independent prognostic factor for disease-free survival in surgically treated patients (P = .01). Specifically, patients with high mIS(b) score showed longer progression-free survival than other subgroups in the TNT cohort (P = .049), but no significant difference was found in the CRT population. Conclusions: In this study, mIS(b) demonstrated significant prognostic value in patients with LARC receiving preoperative therapies, especially in the TNT subgroup. These findings may help tailor the intensity of neoadjuvant therapy for patients.

Background Despite major advancements, effective treatment for patients with SMARCB1-deficient cancers has remained elusive. Here, we report the first case of a SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to a PD-1 inhibitor, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation. Case presentation A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8–12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared. Conclusion SMARCB1‑deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.

PURPOSE:We sought to determine the association between multidisciplinary team (MDT) quality and survival of patients with locally advanced rectal cancer. METHODS:In a post hoc analysis of the randomized phase III STELLAR trial, 464 patients with distal or middle-third, clinical tumor category cT3-4 and/or regional lymph node-positive rectal cancer who completed surgery were evaluated. Disease-free survival (DFS) and Overall survival (OS) were stratified by Multidisciplinary team (MDT) quality, which was also included in the univariable and multivariable analyses of DFS and OS. RESULTS:According to the univariable analyses, a significantly worse DFS was associated with a fewer specialized medical disciplines participating in MDT (<5 vs ≥ 5; P=0.049),a lower frequency of MDT meetings ( 200; P=0.039). In addition, a lower number of specialized medical disciplines participating in MDT (<5 vs ≥ 5; P<0.001), a lower frequency of MDT meetings ( 200; P=0.001) were the variables associated with OS. These 3 factors were considered when assessing MDT quality, which was classified into 2 categories: high quality or general quality. Patients treated in hospitals with high MDT quality had longer 3-year OS (90.5 % vs 78.1 %; P=0.001) and similar 3-year DFS (70.3 % vs 61.3 %; P=0.109) compared to those treated in hospitals of the general MDT quality group. Furthermore, multivariable analyses revealed a significance for DFS (HR, 1.648; 95 % CI, 1.143-2.375; P=0.007) and OS (HR, 2.771; 95 % CI, 1.575-4.877; P<0.001) in MDT quality. CONCLUSIONS:The use of hospitals with optimized multidisciplinary infrastructure had a significant influence on survival of patients with locally advanced rectal cancer.

As the global incidence of cancer continues to rise rapidly, the need for swift and precise diagnoses has become increasingly pressing. Pathologists commonly rely on H&E-panCK stain pairs for various aspects of cancer diagnosis, including the detection of occult tumor cells and the evaluation of tumor budding. Nevertheless, conventional chemical staining methods suffer from notable drawbacks, such as time-intensive processes and irreversible staining outcomes. The virtual stain technique, leveraging generative adversarial network (GAN), has emerged as a promising alternative to chemical stains. This approach aims to transform biopsy scans (often H&E) into other stain types. Despite achieving notable progress in recent years, current state-of-the-art virtual staining models confront challenges that hinder their efficacy, particularly in achieving accurate staining outcomes under specific conditions. These limitations have impeded the practical integration of virtual staining into diagnostic practices. To address the goal of producing virtual panCK stains capable of replacing chemical panCK, we propose an innovative multi-model framework. Our approach involves employing a combination of Mask-RCNN (for cell segmentation) and GAN models to extract cytokeratin distribution from chemical H&E images. Additionally, we introduce a tailored dynamic GAN model to convert H&E images into virtual panCK stains, integrating the derived cytokeratin distribution. Our framework is motivated by the fact that the unique pattern of the panCK is derived from cytokeratin distribution. As a proof of concept, we employ our virtual panCK stains to evaluate tumor budding in 45 H&E whole-slide images taken from breast cancer-invaded lymph nodes . Through thorough validation by both pathologists and the QuPath software, our virtual panCK stains demonstrate a remarkable level of accuracy. In stark contrast, the accuracy of state-of-the-art single cycleGAN virtual panCK stains is negligible. To our best knowledge, this is the first instance of a multi-model virtual panCK framework and the utilization of virtual panCK for tumor budding assessment. Our framework excels in generating dependable virtual panCK stains with significantly improved efficiency, thereby considerably reducing turnaround times in diagnosis. Furthermore, its outcomes are easily comprehensible even to pathologists who may not be well-versed in computer technology. We firmly believe that our framework has the potential to advance the field of virtual stain, thereby making significant strides towards improved cancer diagnosis.

INTRODUCTION:Lymph node metastasis is one of the most common ways of tumour metastasis. The presence or absence of lymph node involvement influences the cancer's stage, therapy, and prognosis. The integration of artificial intelligence systems in the histopathological diagnosis of lymph nodes after surgery is urgent. METHODS:Here, we propose a pan-origin lymph node cancer metastasis detection system. The system is trained by over 700 whole-slide images (WSIs) and is composed of two deep learning models to locate the lymph nodes and detect cancers. RESULTS:It achieved an area under the receiver operating characteristic curve (AUC) of 0.958, with a 95.2% sensitivity and 72.2% specificity, on 1,402 WSIs from 49 organs at the National Cancer Center, China. Moreover, we demonstrated that the system could perform robustly with 1,051 WSIs from 52 organs from another medical centre, with an AUC of 0.925. CONCLUSION:Our research represents a step forward in a pan-origin lymph node metastasis detection system, providing accurate pathological guidance by reducing the probability of missed diagnosis in routine clinical practice.

Abstract Background For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. Methods This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local–regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. Discussion This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. Trial registration This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

The identification a signature comprising a group of genes as markers of cancer response to chemoradiotherapy would be more appropriate and effective for predicting chemoradiotherapy efficacy. This study investigated the differentially expressed genes (DEGs) related to chemoradiotherapy resistance and established a multigene expression model for predicting the sensitivity of rectal cancer to chemoradiotherapy in rectal cancer patients, elucidated the mechanism of resistance to synchronized chemoradiotherapy. The genome-wide expression profiling microarray were performed in the tissues of 81 rectal cancer patients before neoadjuvant therapy to analyze and discover DEGs related to chemoradiotherapy resistance, and the results were verified in 45 rectal cancer patients, and finally a 20-gene signature was proposed to be a predictor of chemoradiotherapy response. Molecular biology experiments revealed that zinc finger protein 37A (ZNF37A) downregulation leads to therapeutic resistance. This study identified a 20-gene signature with group of genes can help predict the response to chemoradiotherapy of rectal cancer patients. ZNF37A demonstrated a statistically significant correlation with sensitivity to chemoradiotherapy and survival in patients with LARC who underwent chemoradiotherapy. The findings revealed that ZNF37A bound to the tumor necrosis factor receptor superfamily member 6B (TNFRSF6B) promoter region, thereby suppressing its transcriptional activity. Reduced expression of ZNF37A induces chemoradiation resistance by inhibiting apoptosis in colorectal cancer (CRC) cells. TNFRSF6B Knockdown restored the sensitivity of CRC to chemoradiotherapy. ZNF37A is an effective modulator of chemoradiotherapy response in rectal cancer. These findings elucidate the molecular mechanism underlying chemoradiotherapy resistance and provide potential applications for individualized clinical therapy.

Background The tumour-draining lymph node (TDLN) plays a pivotal role in the suppression of malignant tumour, however, the immunological profile and prognostic differences between large TDLN (L-TDLN) and small TDLN (S-TDLN) in colorectal cancer (CRC) remain unclear. Methods We conducted a study using data from the Chinese National Cancer Center (CNCC) database, identifying 837 CRC patients with non-metastatic TDLN, and categorised them into L-TDLN and S-TDLN groups. The long-term survival outcomes and adjuvant therapy efficacy were compared between the two groups. Furthermore, we evaluated the differences in immune activation status and immune cell subsets between patients in L-TDLN and S-TDLN groups by RNA sequencing and immunohistochemical (IHC) staining. Results Patients with L-TDLN demonstrated better long-term outcomes compared to those with S-TDLN. Among patients with L-TDLN, there was no significant difference in long-term outcomes between those who received adjuvant chemotherapy and those who did not. The RNA sequencing data revealed a wealth of immune-activating pathways explored in L-TDLN. Furthermore, IHC analysis demonstrated higher numbers of CD3+ and CD8 + T cells in L-TDLN and the corresponding CRC lesions, as compared to patients with S-TDLN. Conclusion Enlarged TDLN exhibited an activated anti-tumour immune profile and may serve as an indicator for favourable survival in non-metastatic CRC.