Accurate prediction of tumour response to neoadjuvant chemoradiotherapy enables personalised perioperative therapy for locally advanced rectal cancer. We aimed to develop and validate an artificial intelligence radiopathomics integrated model to predict pathological complete response in patients with locally advanced rectal cancer using pretreatment MRI and haematoxylin and eosin (H&E)-stained biopsy slides. In this multicentre observational study, eligible participants who had undergone neoadjuvant chemoradiotherapy followed by radical surgery were recruited, with their pretreatment pelvic MRI (T2-weighted imaging, contrast-enhanced T1-weighted imaging, and diffusion-weighted imaging) and whole slide images of H&E-stained biopsy sections collected for annotation and feature extraction. The RAdioPathomics Integrated preDiction System (RAPIDS) was constructed by machine learning on the basis of three feature sets associated with pathological complete response: radiomics MRI features, pathomics nucleus features, and pathomics microenvironment features from a retrospective training cohort. The accuracy of RAPIDS for the prediction of pathological complete response in locally advanced rectal cancer was verified in two retrospective external validation cohorts and further validated in a multicentre, prospective observational study (ClinicalTrials.gov, NCT04271657). Model performances were evaluated using area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Between Sept 25, 2009, and Nov 3, 2017, 303 patients were retrospectively recruited in the training cohort, 480 in validation cohort 1, and 150 in validation cohort 2; 100 eligible patients were enrolled in the prospective study between Jan 10 and June 10, 2020. RAPIDS had favourable accuracy for the prediction of pathological complete response in the training cohort (AUC 0·868 [95% CI 0·825-0·912]), and in validation cohort 1 (0·860 [0·828-0·892]) and validation cohort 2 (0·872 [0·810-0·934]). In the prospective validation study, RAPIDS had an AUC of 0·812 (95% CI 0·717-0·907), sensitivity of 0·888 (0·728-0·999), specificity of 0·740 (0·593-0·886), NPV of 0·929 (0·862-0·995), and PPV of 0·512 (0·313-0·710). RAPIDS also significantly outperformed single-modality prediction models (AUC 0·630 [0·507-0·754] for the pathomics microenvironment model, 0·716 [0·580-0·852] for the radiomics MRI model, and 0·733 [0·620-0·845] for the pathomics nucleus model; all p<0·0001). RAPIDS was able to predict pathological complete response to neoadjuvant chemoradiotherapy based on pretreatment radiopathomics images with high accuracy and robustness and could therefore provide a novel tool to assist in individualised management of locally advanced rectal cancer. National Natural Science Foundation of China; Youth Innovation Promotion Association of the Chinese Academy of Sciences.

The revolution in cancer immunotherapy, particularly through immune checkpoint inhibitors (ICIs), underscores the significant role of the tumor microenvironment (TME) in determining therapeutic outcomes. At the heart of this is the classification of tumors into “cold” and “hot”, which significantly influences the efficacy of immunotherapy. “Cold” tumors are characterized by scant immune cell infiltration and an immunosuppressive TME, which effectively evades immune detection and resists ICIs. In contrast, “hot” tumors, characterized by abundant immune cells and a proinflammatory environment, are more receptive to immunotherapeutic approaches. This review comprehensively examines the molecular and cellular foundations of the “cold” tumor phenotype, delving into the mechanisms of camouflage (impeding immune priming and infiltration), coercion (suppressing immune functions)​​, and ​​cytoprotection (resisting inflammatory death)​​ that contribute to maintaining immune silence. Furthermore, it critically evaluates emerging strategies for converting “cold” tumors to “hot”, immune-reactive entities, including the role of biomaterials in remodeling the TME to increase the effectiveness of immunotherapy. Through an in-depth exploration of these foundational mechanisms and therapeutic advancements, this review seeks to shed light on the way forward in cancer treatment, framing the transformation of “cold” tumors to “hot” tumors as a crucial approach to enhancing the reach of immunotherapy to a broader array of cancer types.

Background: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. Materials and Methods: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. Results: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1–3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. Conclusion: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. Implications for Practice: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1–3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.