Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC.Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs).Results: Five Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected.Conclusions: The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.

Background: An increasing number of studies have turned their lens to the application of Artificial Intelligence (AI) in the diagnosis and treatment of colorectal cancer (CRC).Objective: To clarify and visualize the basic situation, research hotspots, and development trends of AI in the diagnosis and treatment of CRC, and provide clues for research in the future.Methods: On January 31, 2024, the Web of Science Core Collection (WoSCC) database was searched to screen and export the relevant research published during 2004-2023, and Cite Space, VoSviewer, Bibliometrix were used to visualize the number of publications, countries (regions), institutions, journals, authors, citations, keywords, etc.Results: A total of 2715 pieces of literature were included. The number of publications grew slowly until the end of 2016, but rapidly after 2017, till to the peak of 798 in 2023. A total of 92 countries, 3997 organizations, and 15,667 authors were involved in this research. Chinese scholars released the highest number of publications, and the U.S. contributed the highest number of total citations. As to authors, MORI, YUICHI had the highest number of publications, and WANG, PU had the highest number of total citations. According to the analysis of citations and keywords, the current research hotspots are mainly related to “Colonoscopy”, “Polyp Segmentation”, “Digital Pathology”, “Radiomics”, “prognosis”.Conclusion: Research on the application of AI in the diagnosis and treatment of CRC has made significant progress and is flourishing across the world. Current research hotspots include AI-assisted early screening and diagnosis, pathology, and staging, and prognosis assessment, and future research is predicted to put weight on multimodal data fusion, personalized treatment, and drug development.

Currently, conventional neoadjuvant therapy or postoperative adjuvant therapy, such as chemotherapy and radiation therapy, can only bring limited survival benefits to gastric cancer (GC). Median survival after palliative chemotherapy is also low, at about 8–10 months. Immunotargeting is a new option for the treatment of GC, but has not been widely replicated. The highly immunosuppressed tumor microenvironment (TME) discounts the efficacy of immunotherapy for GC. Therefore, new strategies are needed to enhance the immune response of the TME. This paper reviewed the relationship between microorganisms and GC, potential links between microorganisms and immunotherapy and research of microorganisms combined immunotherapy.

Background: Colorectal cancer (CRC) is a heterogeneous cancer. Its treatment depends on its anatomical site and molecular features. Carcinomas of the rectosigmoid junction are frequent; however, specific data on these tumors are sparse, as they are frequently assigned to either the colon or rectum. This study sought to identify the molecular features of rectosigmoid junction cancer to determine whether there should be any difference between the therapeutic management of rectosigmoid junction cancer and that of sigmoid colon or rectum cancer. Methods: The data of 96 CRC patients with carcinomas in the sigmoid colon, rectosigmoid junction, and rectum were retrospectively summarized. The next-generation sequencing (NGS) data of the patients were analyzed to study the molecular characteristics of the carcinomas in different locations of the bowel. Results: In total, there was no difference in the clinicopathologic characteristics of the three groups. TP53, APC, and KRAS genes were the top 3 alteration genes in sigmoid colon, rectosigmoid junction, and rectum cancer. The rates of the KRAS, NRAS, and PIK3CA increased as the location moved distally, while the rates of APC and BRAF decreased. Almost no significant molecular differences were found among the three groups. The prevalence of the FLT3, fms-related tyrosine kinase 1 (FLT1), and phosphoenolpyruvate carboxykinase 1 (PCK1) mutation was lower in the rectosigmoid junction group than the sigmoid colon and rectum groups (P>0.05). The proportion of the transforming growth factor beta pathway was higher in the rectosigmoid junction and rectum groups than the sigmoid colon group (39.3% vs. 34.3% vs. 18.2%, respectively, P=0.121, P=0.067, P=0.682); a higher proportion of MYC pathway was also observed in the rectosigmoid junction than that in rectum and sigmoid colon (28.6% vs. 15.2% vs. 17.1%, P=0.278, P=0.202, P=0.171). Regardless of the clustering method employed, the patients were divided into two clusters, and the composition of clusters revealed no significant differences in terms of the different locations. Conclusions: Rectosigmoid junction cancer has a distinctive molecular profile compared to the molecular profiles of the adjacent bowel segment cancers.