Non-small cell lung cancer (NSCLC) with driver mutations, notably epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase, shows reduced sensitivity to immune checkpoint inhibitors. A subgroup analysis of the IMpower150 data on patients resistant to EGFR tyrosine kinase inhibitors (EGFR-TKI) before enrollment demonstrated prolonged progression-free survival (PFS) with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) over bevacizumab, carboplatin, and paclitaxel. However, due to the exploratory nature and small sample size, the efficacy of ABCP post-EGFR-TKI failure is still debated. We evaluated ABCP therapy against other platinum-based regimens without immune checkpoint inhibitors in terms of effectiveness and toxicity.

Data from patients with advanced or recurrent NSCLC harboring EGFR-sensitizing mutations treated with platinum-based chemotherapy or ABCP at five Japanese hospitals were retrospectively analyzed. Propensity score matching compared efficacy outcomes, including overall response rate (ORR), PFS, and OS.

Of 183 EGFR mutation carriers, 33 underwent ABCP therapy, while 150 received platinum-based chemotherapy. Following propensity score matching, 32 and 74 patients were analyzed. In the ABCP group, median PFS and OS were 6.8 and 16.7 months compared to 5.8 and 25.7 months with platinum-based chemotherapy, showing no significant differences in PFS (p = 0.46) and OS (p = 0.85). In liver metastases, ABCP yielded a median PFS of 9.9 versus 6.1 months and an ORR of 62.5 % versus 35.7 % relative to platinum-based chemotherapy, without statistical significance (PFS p = 0.16; ORR p = 0.70).

Compared with platinum-based chemotherapy, ABCP did not improve effectiveness in patients with EGFR-mutated NSCLC after EGFR-TKI failure.

With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.

Esophageal cancer is a type of digestive system tumor with a high degree of malignancy. In recent years, research has been conducted on immunotherapy, chemotherapy and radiation therapy for esophageal cancer. However, there are still shortcomings in the improvement of 5-year survival rates. In order to explore more therapy options, the present study evaluated the efficacy and safety of recombinant human-endostatin (rh-endostatin) combined with sintilimab and chemotherapy for the first-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). This retrospective study included data from 31 patients with unresectable locally advanced or metastatic esophageal cancer treated between January 2019 and December 2023, and was approved by the First Affiliated Hospital of Nanjing Medical University (Nanjing, China). All patients received first-line treatment combining rh-endostatin with sintilimab, paclitaxel liposome and platinum. Following the completion of 6 cycles, maintenance therapy with sintilimab was administered until disease progression occurred. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) time, overall survival (OS) time and adverse events (AEs) were observed. Symptomatic or supportive care was administered as needed, according to the clinical discretion of the treating physician. As of July 17, 2024, the median follow-up time was 13.07 months, with a median PFS time of 8.30 months (95% confidence interval, 3.442-13.158 months). For these 31 patients, the ORR was 67.7% (21/31), while the DCR was 93.5% (29/31). The median OS time reached 23.07 months. Furthermore, 77.4% of patients experienced at least one treatment-related AE (TRAE), and grade 3 TRAEs occurred in 8 patients (25.8%). No unexpected AEs were observed. In conclusion, rh-endostatin combined with sintilimab and chemotherapy exhibited positive efficacy and safety in patients with advanced ESCC, providing a promising treatment regimen for these patients.

Angiogenesis is a crucial process in lung cancer growth and progression. Heat shock protein family D member 1 (HSPD1 or HSP60) plays a significant role in promoting lung cancer development, but its role in angiogenesis remains largely unexplored. The present study aimed to investigate the involvement of HSPD1 in lung cancer cell-induced angiogenesis using indirect co-culture experiments. Secretomes were collected from stable HSPD1-knockdown A549 lung cancer cells [short hairpin (sh)HSPD1-A549 cells] and scramble control cells (shControl-A549 cells) and used to treat human endothelial EA.hy926 cells. Effects of the secretomes on key steps of angiogenesis, including endothelial cell proliferation, migration, invasion, aggregation and tube formation, were assessed using BrdU incorporation, wound healing, Transwell invasion, hanging-drop and Matrigel tube formation assays, respectively. The amount of vascular endothelial growth factor (VEGF) secreted by EA.hy926 cells was determined using ELISA. The correlation of VEGFA expression with HSPD1 expression and overall survival in patients with lung adenocarcinoma was evaluated using bioinformatics analysis. The results revealed that the shControl-A549 secretome markedly stimulated endothelial cell proliferation, migration, invasion, aggregation, tube formation and VEGF secretion, whereas the shHSPD1-A549 secretome had no significant effects on these processes. VEGFA expression was markedly associated with HSPD1 expression and overall survival in patients with lung adenocarcinoma. In conclusion, the findings highlighted the role of HSPD1 in promoting angiogenesis capability of endothelial cells, potentially through VEGF-mediated pathways. Targeting HSPD1 may represent a promising therapeutic strategy to inhibit angiogenesis and improve clinical outcomes in lung cancer patients.

NCT06203600.

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein-Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.

Current challenges in Chimeric Antigen Receptor (CAR) -T cell therapy for hematological cancers include T cell exhaustion and limited persistence, which contribute to cancer relapse.

The effects of Axitinib, a VEGFR inhibitor, on the biological functions of CAR-T cells in vitro and in vivo were investigated by comparing CAR-T cells pre-treated ex vivo with Axitinib, as well as utilizing a B-ALL mouse model. Real-time quantitative PCR and Western blotting were employed to detect the expression of molecules related to differentiation, exhaustion, and the Wnt pathway in CAR-T cells. Flow cytometry was used to assess changes in CAR-T cell differentiation, exhaustion, activation, apoptosis, proliferation, and cytokine secretion. Western blotting and flow cytometry were used to assess changes in VEGFR expression. Bioluminescence imaging, flow cytometry, and immunohistochemistry (IHC) analysis were used to evaluate changes in tumor burden in mice receiving different treatments, while hematoxylin and eosin (H&E) staining were used to monitor histological changes in the liver and spleen of mice.

Axitinib treatment notably reduced CAR-T cell exhaustion and terminal differentiation both under tonic signaling and tumor antigen exposure scenarios. Furthermore, CAR-T cells pretreated with Axitinib demonstrated enhanced anti-tumor efficacy and prolonged survival in vivo. Mechanistically, Axitinib treatment upregulated the Wnt/β-catenin signaling pathway in CAR-T cells. Using agonists/inhibitors of the Wnt/β-catenin pathway could respectively mimic or counteract the effects of Axitinib on CAR-T cell exhaustion and differentiation. CAR-T cells treated with Axitinib can inhibit the VEGFR2 pathway. CAR-T cells treated with anti-VEGFR2 antibody can activate the Wnt/β-catenin pathway and prevent CAR-T cell exhaustion.

Axitinib confers resistance to exhaustion in CAR-T cells by modulating the Wnt/β-catenin signaling pathway.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

Clinical trials have shown that neoadjuvant anlotinib combined with PD-1 blockade therapy can prolong the survival of patients with driver gene negative non-small cell lung cancer (NSCLC), but some patients fail to benefit from the combination therapy.

To explore the potential drug resistance mechanism and predict the efficacy of neoadjuvant therapy in NSCLC patients, we used scRNA-seq to observe and analyze the dynamic changes of immune cells, stromal cells and cancer cells in NSCLC patients who received neoadjuvant combination therapy. We analyzed transcriptome data of ~ 47,000 single cells from 9 NSCLC patients, including 3 treatment naïve patients, 3 post-treatment patients with major pathological response (MPR), and 3 Non-MPR patients. Subsequently, the infiltration of immune cells was detected by immunohistochemistry and multiplex immunofluorescence in NSCLC.

In MPR patients, we found that neoadjuvant therapy reduced the expression of the T cell exhausted signature, reduced the transition of T_THEMIS cells to Tregs, and enhanced the positive feedback between CD4+ T cells and PAX5+ memory B cells. In Non-MPR patients, tumor-associated macrophages (TAMs) dampen therapeutic efficiency by being the hub of cell communication. TAMs and fibroblasts stimulate endothelial cells via VEGF, endothelial ZEB1 may up-regulate FLT1 (VEGFR) expression in response to anlotinib, and VEGFR+ endothelial cell signature can predict survival of NSCLC cohort in TCGA. In addition, PLA2G4A, the key enzyme in the VEGF pathway, was highly expressed in the tumor cells of Non-MPR patients after anlotinib treatment. In 135 NSCLC patients, we confirmed by immunohistochemistry that PLA2G4A was positively correlated with poor prognosis and Tregs infiltration.

In conclusion, VEGF signaling dependent dynamic changes in endothelial and epithelial cells are deeply involved in the formation of anlotinib resistance and immunosuppression phenotypes in NSCLC patients.

Over the past few years, immune checkpoint inhibitors resulted in magnificent and durable successes in treating cancer; however, only a minority of patients respond favorably to the treatment due to a broad-spectrum of tumor-intrinsic and tumor-extrinsic factors. With the recent insights gained into the mechanisms of resistance, combination treatment strategies to overcome the resistance and enhance the therapeutic potential of immune checkpoint inhibitors are emerging and showing promising results in both pre-clinical and clinical settings. This has been derived through multiple interconnected mechanisms such as enhancing tumor immunogenicity, improving neoantigen processing and presentation in addition to augmenting T cell infiltration and cytotoxic potentials. In the clinical settings, several avenues of combination treatments involving immune checkpoint inhibitors were associated with considerable improvement in the therapeutic outcome in terms of patient's survival and tumor growth control. This, in turn, increased the spectrum of cancer patients benefiting from the unprecedented and durable effects of immune checkpoint inhibitors leading to their adoption as a first-line treatment for certain cancers. Moreover, the significance of precision medicine in cancer immunotherapy and the unmet demand to develop more personalized predictive biomarkers and treatment strategies are also highlighted in this review.

Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME's complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.

The advent of immune checkpoint blockade (ICB) has transformed cancer immunotherapy, enabling remarkable long-term outcomes and improved survival, particularly with ICB combination treatments. However, clinical benefits remain confined to a subset of patients, and life-threatening immune-related adverse effects pose a significant challenge. This limited efficacy is attributed to cancer heterogeneity, which is mediated by ligand-receptor interactions, exosomes, secreted factors, and key transcription factors. Oncogenic regulators like E2F1 and MYC drive metastatic tumor environments and intertwine with immunoregulatory pathways, impairing T cell function and reducing immunotherapy effectiveness. To address these challenges, FDA-approved biomarkers, such as tumor mutational burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression, help to identify patients most likely to benefit from ICB. Yet, current biomarkers have limitations, making treatment decisions difficult. Recently, T cells-the primary target of ICB-have emerged as promising biomarkers. This review explores the relationship between cancer drivers and immune response, and emphasizes the role of CD8+ T cells in predicting and monitoring ICB efficacy. Tumor-infiltrating CD8+ T cells correlate with positive clinical outcomes in many cancers, yet obtaining tumor tissue remains complex, limiting its practical use. Conversely, circulating T cell subsets are more accessible and have shown promise as predictive biomarkers. Specifically, memory and progenitor exhausted T cells are associated with favorable immunotherapy responses, while terminally exhausted T cells negatively correlate with ICB efficacy. Ultimately, combining biomarkers enhances predictive accuracy, as demonstrated by integrating TMB/PD-L1 expression with CD8+ T cell frequency. Computational models incorporating cancer and immune signatures could further refine patient stratification, advancing personalized immunotherapy.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.

Despite numerous meta-analyses comparing the efficacy and safety of immunotherapy-based combination therapies, the optimal therapeutic combinations remain unclear. This study aims to evaluate the optimal application of all immunotherapy-based combination therapy for advanced/metastatic renal cell carcinoma, focusing on efficacy and safety.

We systemically searched the Web of Science, Cochrane Library, and PubMed for studies regarding the first-line immunotherapy-based combination therapy in patients with advanced or metastatic renal cell carcinoma until April 15, 2024. We used network meta-analysis using a random effect model to facilitate direct and indirect treatment comparisons across outcomes.

Seven clinical studies, including 5542 patients with metastatic renal cell carcinoma, were included in the network meta-analysis analysis. Regarding progression-free survival and overall survival, combined Toripalimab + Axitinib significantly outperformed other immunotherapy-based combination therapies. This regimen significantly improved progression-free survival in the intermediate/poor risk group when stratified by prognosis prediction risks compared to sunitinib alone. For the objective response rate, Avelumab + Axitinib was the most preferred strategy in the favorable-risk group, while Nivolumab + Cabozantinib was favored in the intermediate/poor-risk group compared to other immunotherapy-based combinations. The combinations of Nivolumab + Ipilimumab and Atezolizumab + Bevacizumab had favorable safety profiles.

Immunotherapy-based combination therapies significantly improved progression-free survival, overall survival and objective response rate in patients with metastatic renal cell carcinoma compared to sunitinib monotherapy. However, careful monitoring and personalized treatment strategies are required to balance efficacy and safety in patients with underlying conditions. Future research should focus on optimizing treatment protocols and elucidating the mechanisms of adverse events.

Tumor microvasculature is an important component of the tumor microenvironment (TME), and it has been reported that tumor microvasculature induces TME to become immunosuppressive via vascular endothelial growth factor. However, the significance of this in adenocarcinoma with epidermal growth factor receptor (EGFR) common mutations has not been fully investigated.

We analyzed 262 patients with adenocarcinoma harboring EGFR common mutations who underwent surgery at Kyushu University Hospital between 2006 and 2021. Microvessel density (MVD) was calculated by CD34 immunohistochemistry. Patients were categorized into high and low MVD status, which was compared with the clinicopathological characteristics.

A total of 136 (51.9%) patients had L858R mutation, and 126 (48.1%) had Exon 19 Del. Regarding MVD status; 133 patients (50.8%) were classified as high and 129 (49.2%) as low. Fisher's exact test revealed a significant association of high MVD status with high CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0187), low GZMB+ TILs (p = 0.0019), and high Foxp3+ TILs (p = 0.0003). On multivariate analysis, MVD status was significantly associated with Foxp3+ TILs and GZMB+ TILs. Fisher's exact test also revealed that tumors with L858R mutation had a high MVD status (p = 0.0136) compared with tumors with deletions of exon 19 (Exon 19 Del), and multivariate analysis revealed that L858R mutation was significantly associated with high MVD status.

In adenocarcinomas harboring EGFR common mutations, abundant tumor microvasculature might induce the TME to be immunosuppressive. Tumors with L858R mutation compared with Exon 19 Del might be more likely to form an immunosuppressive TME owing to the abundance of tumor microvasculature.

Lenvatinib is an orally available multi-tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling. These inhibitory activities of lenvatinib exhibit antitumor efficacy, mainly due to their repressive effects on angiogenesis. In addition, a recent non-clinical evaluation using mouse tumor models revealed that lenvatinib causes immunomodulatory effects, including activation of effector T-cells and regulation of tumor-associated macrophages (TAMs). Combined treatment with lenvatinib and anti-programmed cell death-1 antibody (anti-PD-1) resulted in enhanced antitumor activity relative to monotreatment with anti-PD-1 or lenvatinib. This review summarizes the antitumor mechanisms of lenvatinib and of lenvatinib plus anti-PD-1 combination therapy.

Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.

Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade (ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration (FDA) for clinical treatment. However, limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.

Numerous studies have reported vascular endothelial growth factor A (VEGF-A) has a significant impact on the pathophysiology of COVID-19. The objective of this systematic review and meta-analysis is to determine the prognostic value of increased levels of VEGF-A in individuals with COVID-19. A systematic literature search was conducted across multiple electronic databases, including PubMed, Web of Science, Cochrane Library, Scopus, EMBASE, and Google Scholar, up to January 2024. Studies examining the levels of VEGF-A in the serum or plasma of COVID-19 patients were incorporated, with specific attention given to contrasting severe/critical cases against moderate cases. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated using a random-effects model to determine overall effect sizes. Meta-regressions and subgroup analyses were performed to explore potential sources of heterogeneity. The meta-analysis synthesized data from 11 studies involving a total of 1119 COVID-19 patients. Elevated levels of VEGF-A were significantly associated with disease severity, with a pooled SMD of 0.525 (95% CI 0.239-0.058; P = 0.028). Research has indicated that the nature of the relationship differs among various age groups, and there were minor discrepancies in the techniques employed to obtain VEGF-A measurements. Furthermore, meta-regression analysis indicated a potential correlation between VEGF-A levels and assay technique and body mass index (BMI). This meta-analysis provides compelling evidence for the prognostic potency of VEGF-A in COVID-19. Understanding the intricate interplay between VEGF-A and COVID-19 pathophysiology holds promise for the development of targeted therapeutic strategies and prognostic indicators in the management of COVID-19.

Antibody discovery is a lengthy and labor-intensive process, requiring extensive laboratory work to ensure that an antibody demonstrates the appropriate efficacy, production, and safety characteristics necessary for its use as a therapeutic agent in human patients. Traditionally, this process begins with phage display or B-cells isolation campaigns, where affinity serves as the primary selection criterion. However, the initial leads identified through this approach lack sufficient characterization in terms of developability and epitope definition, which are typically performed at late stages. In this study, we present a pipeline that integrates early-stage phage display screening with AI-based characterization, enabling more informed decision-making throughout the selection process. Using immune checkpoints TIM3 and TIGIT as targets, we identified five initial leads exhibiting similar binding properties. Two of these leads were predicted to have poor developability profiles due to unfavorable surface physicochemical properties. Of the remaining three candidates, structural models of the complexes formed with their respective targets were generated for 2: T4 (against TIGIT) and 6E9 (against TIM3). The predicted epitopes allowed us to anticipate a competition with TIM3 and TIGIT binding partners, and to infer the antagonistic functions expected from these antibodies. This study lays the foundations of a multidimensional AI-driven selection of lead candidates derived from high throughput analysis.

Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC). However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI. Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy. Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNAPD-L1@NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy. With NGR-mediated tumor homing and active targeting, Axi/siRNAPD-L1@NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment. Moreover, Axi/siRNAPD-L1@NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNAPD-L1@NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC. Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy.

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited.

A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro.

Patients were divided into TIGAR-positive (n = 80, 20.7%) and -negative (n = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ des-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (p < 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (p = 0.0450), larger number of CD68-positive macrophages (p = 0.0058), larger number of programmed death-ligand 1-positive cases (p = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (p = 0.0004). In vitro, TIGAR knockdown decreased cell motility and induced ferroptosis. TIGAR knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by TIGAR knockdown was inhibited by liproxstatin and baicalein treatment. The combination of TIGAR knockdown and lenvatinib further induced ferroptosis.

High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.

Immune checkpoint inhibitors (ICIs) have been approved for treating various cancers; however, they can cause immune-related adverse events. Generally, ICIs are not associated with an increased risk of infection, however, several reports demonstrated infections caused by non-tuberculous mycobacterium (NTM) during ICI therapy. Here, we report a case of NTM shoulder arthritis with acute exacerbation immediately after ICI initiation. A 75-year-old man was diagnosed with left shoulder arthritis caused by Mycobacterium intracellulare eight months before receiving ICI treatment and was treated with clarithromycin and ethambutol. However, the mild redness, swelling, heat, and shoulder pain persisted. The patient was diagnosed with hepatocellular carcinoma and atezolizumab and bevacizumab treatment was initiated; one day after the initiation of therapy, the patient presented with a fever and worsened shoulder symptoms. Considering the suspected worsening of NTM arthritis, sitafloxacin was additionally administered, and surgical debridement was performed. M. intracellulare was isolated through culturing shoulder synovial tissue; immunohistochemical staining analysis revealed programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) expression in granulation tissue cells. After the arthritis symptoms decreased, atezolizumab plus bevacizumab was resumed and continued with no recurrence of arthritis. The NTM exacerbation on the day after ICI administration suggests the potential involvement of the PD-1/PD-L1 pathway in the pathogenesis of NTM; moreover, adverse inflammatory reactions to NTM were possibly triggered through the blockade of this pathway.

Ivonescimab (AK112) is a first-in-class bispecific antibody that simultaneously targets programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF) with cooperative binding. We report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of ivonescimab in patients suffered from advanced solid tumors.

A multicenter, open-label, dose-escalation, phase I study was conducted in five hospitals in China. Ivonescimab was used as a monotherapy. The dose of ivonescimab intravenously administered was 3, 5, 10, 20, and 30 mg/kg every 2 weeks (Q2W), and 10 and 20 mg/kg every 3 weeks (Q3W). Safety, PK, and PD of ivonescimab were evaluated.

A total of 59 patients treated in the study. Only one dose-limiting toxicity (DLT) occurred in 1 out of 9 patients in the 10 mg/kg Q2W cohort, indicating that no maximum tolerated dose was reached. Among the participants, 53 patients (89.8%) experienced treatment-related adverse events (TRAEs), with the most common being proteinuria (33.9%), aspartate aminotransferase elevation (27.1%), white blood cell count decrease (22.0%), alanine aminotransferase elevation (20.3%), and anemia (20.3%). Fourteen patients (23.7%) had ≥ Grade 3 TRAEs, and 7 patients (11.9%) experienced serious TRAEs. Notably, there were no reported deaths associated with the TRAEs, and no dose-dependent increase in adverse events was observed. The half-life of ivonescimab ranged from 5.0 to 7.3 days following single-dose administration across all dose levels. The serum concentrations of ivonescimab increased with escalating doses in an approximately dose-proportional manner. Following multiple doses, the accumulation ratio ranged from 1.1 to 1.7, suggesting mild accumulation of ivonescimab. The steady state was achieved after 5 doses. Ivonescimab occupancy on PD-1 sustained over 80% across the treatment period. Serum VEGF level was rapidly down-regulated after each administration.

In patients with advanced solid tumors, ivonescimab monotherapy was well-tolerated and demonstrated a linear PK characteristics. PD profiles showed the promising potential of ivonescimab for the management of advanced solid tumors.

ClinicalTrials.gov (NCT04597541).

The immune response is modulated by a diverse array of signals within the tissue microenvironment, encompassing biochemical factors, mechanical forces, and pressures from adjacent tissues. Furthermore, the extracellular matrix and its constituents significantly influence the function of immune cells. In the case of carcinogenesis, changes in the biophysical properties of tissues can impact the mechanical signals received by immune cells, and these signals c1an be translated into biochemical signals through mechano-transduction pathways. These mechano-transduction pathways have a profound impact on cellular functions, influencing processes such as cell activation, metabolism, proliferation, and migration, etc. Tissue mechanics may undergo temporal changes during the process of carcinogenesis, offering the potential for novel dynamic levels of immune regulation. Here, we review advances in mechanoimmunology in malignancy studies, focusing on how mechanosignals modulate the behaviors of immune cells at the tissue level, thereby triggering an immune response that ultimately influences the development and progression of malignant tumors. Additionally, we have also focused on the development of mechano-immunoengineering systems, with the help of which could help to further understand the response of tumor cells or immune cells to alterations in the microenvironment and may provide new research directions for overcoming immunotherapeutic resistance of malignant tumors.

Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.

Lung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Immune checkpoint inhibitors (ICIs) represented by anti-programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) have emerged as a promising frontier in cancer treatment, effectively extending the survival of patients with NSCLC. However, the efficacy of ICIs exhibits significant variability across diverse patient populations, with a substantial proportion showing poor responsiveness and acquired resistance in those initially responsive to ICIs treatments. With the advancement of nanotechnology, nanoparticles offer unique advantages in tumor immunotherapy, including high permeability and prolonged retention(EPR) effects, enhanced drug delivery and stability, and modulation of the inflammatory tumor microenvironment(TME). This review summarizes the mechanisms of resistance to ICIs in NSCLC, focusing on tumor antigens loss and defective antigen processing and presentation, failure T cell priming, impaired T cell migration and infiltration, immunosuppressive TME, and genetic mutations. Furthermore, we discuss how nanoparticles, through their intrinsic properties such as the EPR effect, active targeting effect, shielding effect, self-regulatory effect, and synergistic effect, can potentiate the efficacy of ICIs and reverse resistance. In conclusion, nanoparticles serve as a robust platform for ICIs-based NSCLC therapy, aiding in overcoming resistance challenges.

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.

The efficacy and safety of induction-immunotherapy followed by surgery for unresectable Stage III non-small cell lung cancer (NSCLC) remain challenging. In this open-label, single-center, phase II clinical umbrella trial (ChiCTR2000035367), 100 unresectable Stage III NSCLC patients are enrolled. Patients with PD-L1 expression ≥ 50% but contraindications to anti-angiogenic therapy receive immuno-monotherapy. Patients with PD-L1 expression ≥ 1% and no contraindications to anti-angiogenic therapy receive immunotherapy plus anti-angiogenesis therapy. Patients with PD-L1 expression between 1% and 49%, contraindications to anti-angiogenic therapy, or negative/unknown PD-L1 expression receive chemoimmunotherapy. The primary endpoint is the major pathological response (MPR) rate. Among 47 surgically-treated patients, the MPR rate is 61.7% (95% confidence interval [CI]: 46.4%-75.5%), achieving the prespecified endpoint. For secondary endpoints, the objective response rate for all patients is 54.0% (95% CI: 43.7-64.0). The median event-free survival is 29.9 months (95% CI: 17.0-42.7). Most common adverse event is anemia (49.0%). Exploratory transcriptomic analyses reveal Bone Marrow Stromal Cell Antigen 1 (BST1) as a promising biomarker for response to chemoimmunotherapy. Generally, for unresectable stage III NSCLC patients, anti-PD1 based induction-therapy according to PD-L1 expression and contraindication to antiangiogenic therapy followed by surgery is a feasible option.

Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting immune checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICPs, necessitating to further study the underlying mechanisms of exhaustion. VEGFa, a proangiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICPs, justifying in part the use of an anti-VEGFa mAb, bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICPs. In addition, sCD146 favors protumoral M2-type macrophages and induces the secretion of proinflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with the anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.

This review addresses the current treatment paradigm and new advancements in the management of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) esophagogastric cancer (EGC).

While chemotherapy and surgery remain the cornerstone of EGC treatment, MSI-H/dMMR tumors harbor high tumor mutational burden and represent a subset of patients who benefit from immune checkpoint inhibitors (ICI). ICI has been incorporated in the front line setting with and without chemotherapy for advanced disease. Recently, ICI has been studied in the perioperative setting for resectable disease. Though perioperative ICI results in improved response rates, it is not yet clear whether this translates to a survival benefit. Despite high response rates with ICI in this patient population, many do not respond to therapy, representing a major challenge in treatment. Preclinical studies have highlighted potential mechanisms of resistance which will guide drug development and clinical trials.