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Tremendous progress has been achieved in the field of immune checkpoint inhibitors (ICIs) therapy in lung cancer in recent years. To generate robust, long-lasting anti-tumor immune responses in lung cancer patients, combinational ICI therapies have been explored deeply. Conventionally, chemotherapy was considered as immunosuppressive. It is now recognized that chemotherapy could also reinstate cancer cell immune-surveillance and enable the perception of cancer cells as dangerous. That is to say that chemotherapeutic drugs are not only a source of direct cytotoxic effects but also an adjuvant for anti-tumor immunity. Recently, multiple clinical studies of ICIs combined with chemotherapeutic drugs have been explored and proved effective. However, there are still crucial questions that are not well addressed, such as the optimal dose and schedule for a given combination may differ across disease indications, and the appropriate strategy of selecting patient population that can benefit from ICIs remains unclear. To facilitate more rational lung cancer ICIs therapy development, this review summarizes the immune-regulatory effects and related mechanisms of chemotherapeutic drugs and the clinical progress of ICIs and their combination with chemotherapies in lung cancer treatment.Tremendous progress has been achieved in the field of immune checkpoint inhibitors (ICIs) therapy in lung cancer in recent years. To generate robust, long-lasting anti-tumor immune responses in lung cancer patients, combinational ICI therapies have been explored deeply. Conventionally, chemotherapy was considered as immunosuppressive. It is now recognized that chemotherapy could also reinstate cancer cell immune-surveillance and enable the perception of cancer cells as dangerous. That is to say that chemotherapeutic drugs are not only a source of direct cytotoxic effects but also an adjuvant for anti-tumor immunity. Recently, multiple clinical studies of ICIs combined with chemotherapeutic drugs have been explored and proved effective. However, there are still crucial questions that are not well addressed, such as the optimal dose and schedule for a given combination may differ across disease indications, and the appropriate strategy of selecting patient population that can benefit from ICIs remains unclear. To facilitate more rational lung cancer ICIs therapy development, this review summarizes the immune-regulatory effects and related mechanisms of chemotherapeutic drugs and the clinical progress of ICIs and their combination with chemotherapies in lung cancer treatment.

BRAF V600E‐mutant colorectal cancer (CRC) represents a distinct molecular subtype with considerable heterogeneity in tumor biology and therapeutic response. Although gene expression‐based classifications (BM1/BM2 subtypes) provide valuable insights into underlying molecular and immune features, their clinical application is limited by the need for high‐throughput sequencing. This study aims to establish an immunohistochemistry (IHC)‐based classification system to enable practical subtype stratification and aid prognostic and therapeutic evaluation. Using two independent cohorts (public dataset, n = 218; institutional cohort, n = 122), we performed differential expression analysis, machine learning modeling, and clinical feasibility evaluation. Fourteen candidate markers were identified, and a decision tree algorithm selected CD8 and ARHGEF17 as optimal classifiers. Based on these markers, two IHC‐based subtypes were established: iBM1 (CD8+/ARHGEF17−) and iBM2 (CD8− with any ARHGEF17 expression or CD8+/ARHGEF17+). The IHC‐based subtypes showed concordance with transcriptomic BM subtypes (training: 82.69%, κ = 0.55; validation: 72.22%, κ = 0.44; prospective: 83.33%, κ = 0.57). Transcriptomic profiling revealed enrichment of immune activation and epithelial–mesenchymal transition in iBM1, and cell cycle‐related pathways in iBM2. In clinical validation, iBM1 was associated with poorer survival but greater sensitivity to immune checkpoint inhibitors. This IHC‐based classification provides a practical and accessible approach for BM subtype stratification, reflecting underlying molecular and immune characteristics, and may support prognostic assessment and therapeutic decision‐making in BRAF V600E‐mutant CRC. This study develops an immunohistochemistry (IHC)‐based classification system for BRAF V600E‐mutant colorectal cancer, enabling practical stratification into iBM1 and iBM2 subtypes using CD8 and ARHGEF17 markers. The IHC‐defined subtypes demonstrated concordance with transcriptomic BM1/BM2 classifications and reflected distinct molecular and immune features, with iBM1 associated with poorer prognosis but enhanced responsiveness to immune checkpoint blockade.

Background Radiomics holds great potential for the noninvasive evaluation of EGFR-TKIs and ICIs responses, but data privacy and model robustness challenges limit its current efficacy and safety. This study aims to develop and validate an encrypted multidimensional radiomics approach to enhance the stratification and analysis of therapeutic responses. Materials and methods This multicenter study incorporated various data types from 506 NSCLC patients, which underwent preprocessing through anonymization methods and were securely encrypted using the AES-CBC algorithm. We developed one clinical model and three radiomics models based on clinical factors and radiomics scores (RadScore) of three distinct regions to evaluate treatment response. Additionally, an integrated radiomics-clinical model was created by combining clinical factors with RadScore. The study also explored the association between different EGFR mutations and PD-1/PD-L1 expression in radiomics biomarkers. Findings The radiomics-clinical model demonstrated high performance, with AUC values as follows: EGFR (0.884), 19Del (0.894), L858R (0.881), T790M (0.900), and PD-1/PD-L1 expression (0.893) in the test set. This model outperformed both clinical and single radiomics models. Decision curve analysis further supported its superior clinical utility. Additionally, our findings suggest that the efficacy of EGFR-TKIs and ICIs therapy may not depend on detecting a singular tumor feature or cell type. Conclusion The proposed method effectively balances the level of evidence with privacy protection, enhancing the study’s validity and security. Therefore, radiomics biomarkers are expected to complement molecular biology analyses and guide therapeutic strategies for EGFR-TKIs, ICIs, and their combinations.

Purpose The benefit of immune checkpoint inhibitors’ (ICIs) combination therapy in patients with advanced esophageal squamous cell carcinoma (ESCC) remained unclear. We performed a meta-analysis to explore the efficacy and safety of ICIs’ combination therapy versus chemotherapy alone as first-line treatment in advanced ESCC. Methods A systematic review of randomized controlled trials (RCTs) of ICIs’ combination therapy as first-line treatment in advanced ESCC was conducted via searching PubMed, Embase, and Cochrane database. The data for efficacy and safety of ICIs’ combination therapy were subject to meta-analysis. Subgroup analysis was performed in patients with different PD-L1 expression status. Results A total of 5 RCTs and 3163 patients were included. Overall, the hazard ratio (HR) for overall survival (OS) benefit with ICIs’ combination therapy was 0.68 (95% CI 0.62–0.75) compared with chemotherapy alone. The HR for progression-free survival (PFS) benefit and the odds ratio (OR) for overall response rate (ORR) increase were 0.62 (95% CI 0.56–0.68) and 2.01 (95% CI 1.70–2.38), respectively. The OS and PFS benefits with ICIs’ combination therapy over chemotherapy alone were also observed in the subgroup of PD-L1 positive expression, but not in the subgroup of PD-L1 negative expression. The incidence of grade 3 or higher treatment-related adverse events was 60.4% with ICIs’ combination therapy and 56.3% with chemotherapy alone (OR, 1.19; 95% CI 0.90–1.57). Conclusion ICIs’ combination therapy showed superior OS, PFS, and ORR over chemotherapy alone with a manageable safety profile. These results suggested that ICIs’ combination therapy can be considered as a new first-line treatment for advanced ESCC.

Hepatocellular carcinoma (HCC) is a lethal malignancy with a lack of effective treatments particularly for the disease at an advanced stage. Even though immune checkpoint inhibitors (ICIs) have made great progress in the treatment of HCC, durable and ideal clinical benefits still cannot be achieved in plenty of patients with HCC. Therefore, novel and refined ICI-based combination therapies are still needed to enhance the therapeutic effect. The latest study has reported that the carbonic anhydrase XII inhibitor (CAXIIi), a novel type of anticancer drug, can modify the tumor immunosuppression microenvironment by affecting hypoxic/acidic metabolism and alter the functions of monocytes and macrophages by regulating the expression of C-C motif chemokine ligand 8 (CCL8). These observations shine a light on improving programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapy in combination with CAXIIis. This mini-review aims to ignite enthusiasm to explore the potential application of CAXIIis in combination with immunotherapy for HCC.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.

Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60–70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.

Until the advent of immune checkpoint inhibitors (ICIs), definitive radiotherapy (RT) concurrently with chemotherapy was recommended for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC). The trimodality paradigm with consolidation ICIs following definitive concurrent chemoradiotherapy has been the standard of care since the PACIFIC trial. Preclinical evidence has demonstrated the role of RT in the cancer-immune cycle and the synergistic effect of RT combined with ICIs (iRT). However, RT exerts a double-edged effect on immunity and the combination strategy still could be optimized in many areas. In the context of LA-NSCLC, optimized RT modality, choice, timing, and duration of ICIs, care for oncogenic addicted tumors, patient selection, and novel combination strategies require further investigation. Targeting these blind spots, novel approaches are being investigated to cross the borders of PACIFIC. We discussed the development history of iRT and summarized the updated rationale for the synergistic effect. We then summarized the available research data on the efficacy and toxicity of iRT in LA-NSCLC for cross-trial comparisons to eliminate barriers. Progression during and after ICIs consolidation therapy has been regarded as a distinct resistance scenario from primary or secondary resistance to ICIs, the subsequent management of which has also been discussed. Finally, based on unmet needs, we probed into the challenges, strategies, and auspicious orientations to optimize iRT in LA-NSCLC. In this review, we focus on the underlying mechanisms and recent advances of iRT with an emphasis on future challenges and directions that warrant further investigation. Taken together, iRT is a proven and potential strategy in LA-NSCLC, with multiple promising approaches to further improve the efficacy. 4Fbhb184awiAcRjUX8wa4V Video Abstract

Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune checkpoint blockade (ICB) remains a critical clinical challenge, characterized by variable response rates and non-durable benefits. However, growing research into the complex intrinsic and extrinsic characteristics of tumors has advanced our understanding of the mechanisms behind ICI resistance, potentially improving treatment outcomes. Additionally, robust predictive biomarkers are crucial for optimizing patient selection and maximizing the efficacy of ICBs. Recent studies have emphasized that multiple rational combination strategies can overcome immune checkpoint resistance and enhance susceptibility to ICIs. These findings not only deepen our understanding of tumor biology but also reveal the unique mechanisms of action of sensitizing agents, extending clinical benefits in cancer immunotherapy. In this review, we will explore the underlying biology of ICIs, discuss the significance of the tumor immune microenvironment (TIME) and clinical predictive biomarkers, analyze the current mechanisms of resistance, and outline alternative combination strategies to enhance the effectiveness of ICIs, including personalized strategies for sensitizing tumors to ICIs.

As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.