Advancements in nanomedicine delivery systems: unraveling immune regulation strategies for tumor immunotherapy.

This review highlights the significant role of nanodrug delivery systems (NDDS) in enhancing the efficacy of tumor immunotherapy. Focusing on the integration of NDDS with immune regulation strategies, it explores their transformative impacts on the tumor microenvironment and immune response dynamics. Key advancements include the optimization of drug delivery through NDDS, targeting mechanisms like immune checkpoint blockade and modulating the immunosuppressive tumor environment. Despite the progress, challenges such as limited clinical efficacy and complex manufacturing processes persist. The review emphasizes the need for further research to optimize these systems, potentially revolutionizing cancer treatment by improving delivery efficiency, reducing toxicity and overcoming immune resistance.

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Investigating esophageal sarcomatoid carcinoma and its comparison with esophageal squamous cell carcinoma on clinicopathological characteristics, prognosis, and radiomics features: a retrospective study.

Introduction: Esophageal sarcomatoid carcinoma (ESC) is a rare pathological subtype of esophageal carcinomas, wherein its epithelial component typically demonstrates squamous cell carcinoma (SCC). However, the clinicopathological features and prognosis of ESC remain unclear, alongside its unique aspects compared to esophageal SCC (ESCC). Methods: Between January 2008 and December 2018, we retrospectively reviewed 67 ESC patients treated at West China Hospital. Among them, 51 patients with resected ESC were matched with 98 resected ESCC patients over the same period using propensity score matching at 1:2. The survival time and radiomics features of the two groups were compared. Results: A total of 59 patients with resected ESC and eight patients with non-resected ESC were enrolled. Progression-free survival (PFS) and overall survival (OS) were significantly different in patients with different TNM stages (p < 0.001). A multivariate analysis showed that length of tumor was an independent factor for OS in resetable ESC (p = 0.041). Among matched ESC and ESCC patients, OS was significantly longer for patients with ESC than those with ESCC (5-year OS, 61.1% vs. 43.6%; HR 0.59, 95% CI 0.35-0.96; p = 0.032). A Rad-score for discriminating ESC from ESCC containing two CT-derived radiomics features was developed [area under the curve: 0.823 (95% CI 0.732-0.913) in the training cohort and 0.828 (95% CI 0.636-1.000) in the validation cohort, respectively]. Conclusions: ESC has a better prognosis when compared with ESCC. By developing a radiomics prediction model, we provide reliability and convenience for the differential diagnosis of ESC from ESCC.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC. Methods: The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME). Results: Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8+ T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model. Conclusions: Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.

Prognostic significance of FAT10 expression in malignant tumors: a systematic review and meta-analysis.

Aim: FAT10, a ubiquitin-like modifier protein, influences apoptosis, DNA damage response and tumor growth, with unclear effects on cancer prognosis. Methods: We reviewed FAT10 expression's impact on malignancy prognosis through a systematic review and meta-analysis, including studies up to September 2023 from PubMed, EMBASE and Web of Science. Results: From 18 studies involving 2513 patients, FAT10 overexpression significantly reduced overall and disease-free survival across various tumors, indicating correlations with advanced disease stage, poor differentiation, lymph node metastasis and larger tumor size. Conclusion: FAT10's overexpression suggests a negative prognostic value in cancer, meriting further investigation.PROSPERO Registration Number: CRD42023431287.

This study investigated a protein called FAT10, which is involved in how cells behave, including how cancer cells grow and survive. It analyzed previous research to see if high levels of FAT10 in patients with cancer can help predict how serious their cancer is and how it might progress. After reviewing 18 studies involving 2513 patients, we found that patients with more FAT10 in their cells often had a worse outlook, including a higher chance of the cancer returning and a shorter overall survival time. This pattern existed for different types of cancer. Our findings suggest that measuring FAT10 levels could be helpful for doctors to better understand a patient's cancer and choose the best treatment. However, more studies are needed to confirm our results.

Prognostic value of NOB1 expression levels in various cancers: a systematic review and meta-analysis.

Aim: This study evaluates the prognostic significance of NOB1 expression levels in various cancers. Patients & methods: Studies examining NOB1 expression in cancer, encompassing data from 1694 patients across 14 studies, were analyzed for overall survival (OS) and progression-free survival (PFS) using hazard ratios (HRs) and 95% CIs, and for clinicopathological parameters using relative risks (RRs). Results: High NOB1 expression correlated with shorter OS (HR: 2.12, 95% CI: 1.82-2.48) and PFS (HR: 2.23, 95% CI: 1.62-3.07) and was associated with adverse tumor characteristics such as stage and metastasis. Conclusion: Elevated NOB1 expression in various tumors signifies a poor prognosis, serving as a predictive marker for malignancy outcomes.PROSPERO Register Number: CRD42023394051.

This study looked at how a protein called NOB1 affects cancer. NOB1 is usually found in healthy parts of the body like the lungs and liver, but it might also show up in cancer. We checked data from many sources to see if there's a connection between NOB1 and cancer's severity. After studying 1694 samples from 14 studies, we found that people with more NOB1 in their bodies had a tougher time with cancer. Their disease got worse quicker and they did not live as long as those with less NOB1. Also, higher NOB1 levels were linked to more serious and aggressive cancers. This means that NOB1 could help doctors predict how bad a patient's cancer is and plan treatments better.

Advancements in immunotherapy for advanced esophageal squamous cell carcinoma: a comprehensive review of current strategies and future directions.

INTRODUCTION: Esophageal cancer (EC), particularly esophageal squamous cell carcinoma (ESCC), is characterized by high incidence and poor prognosis worldwide, necessitating novel therapeutic approaches like immunotherapy. This review explores the impact of immune checkpoint inhibitors (ICIs) on ESCC, especially focusing on PD-1/PD-L1 and CTLA-4 inhibitors. Our literature search, conducted across databases including PubMed, Web of Science, and EMBASE, from January 2010 to December 2023, aimed at identifying advancements, challenges, and future directions in the use of immunotherapy for ESCC. AREAS COVERED: We provide a detailed analysis of clinical trials evaluating the efficacy of ICIs as monotherapy and in combination with chemotherapy, radiotherapy, and targeted therapy for locally advanced ESCC. Our findings highlight the significant survival benefits offered by ICIs, albeit with varying efficacy across patient populations, emphasizing the need for precise biomarkers to tailor treatment strategies. EXPERT OPINION: The integration of immunotherapy into the ESCC treatment paradigm represents a significant shift, improving survival outcomes. Future research should focus on optimizing combination therapies and novel immunotherapeutic agents, incorporating genetic and tumor microenvironment analyses to enhance patient selection and treatment efficacy.

Prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) in malignant tumours: a meta-analysis and bioinformatic analysis.

OBJECTIVES: This study aimed to systematically elucidate the prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) expression in various cancers and its correlation with their clinicopathological characteristics. DESIGN: In this meta-analysis and bioinformatic analysis, articles were identified through searches of multiple databases and meta-analysed according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. Data from The Cancer Genome Atlas were examined using UCSC Xena tools to further confirm the prognostic effect of CKS2. DATA SOURCES: The PubMed, Embase, Web of Science and Cochrane Library databases were searched for articles published from their inception to 1 January 2023, using a combination of subject terms and free words, including 'CKS2', 'cancer', 'tumor', 'neoplasm', 'carcinoma', 'malignancy' and 'prognosis'. ELIGIBILITY CRITERIA: The analysis included cohort or case-control studies, reported in English, with malignancy diagnoses confirmed by pathological methods, available HRs and 95% CIs for overall survival (OS) or extractable Kaplan-Meier curves, and a sample size of ≥20 patients. Reviews, commentaries, letters, conference reports, case reports, in vitro and animal studies, studies of CKS2 gene variants, studies with sample cases from public databases and studies with unavailable survival or duplicated data were excluded. DATA EXTRACTION AND SYNTHESIS: Two researchers independently screened the articles, extracted the data and evaluated the quality of included studies using the Newcastle-Ottawa Scale. Meta-analysis and bioinformatic analyses were performed using the STATA and R software, respectively. RESULTS: The analysis included 13 retrospective studies encompassing 1348 cases across 10 cancer types. Nine studies involving 1124 patients examined the correlation between CKS2 expression levels and OS. A fixed-effects model analysis revealed a significant association between high CKS2 expression and reduced OS (HR=2.27, 95% CI=1.87 to 2.77, p<0.001). Furthermore, high CKS2 expression was significantly associated with advanced tumour stage (relative risk (RR) = 1.82, 95% CI=1.57 to 2.11, p<0.001), lymph node metastasis (RR=1.68, 95% CI=1.38 to 2.04, p<0.001), larger tumour size (RR=1.60, 95% CI=1.27 to 2.03, p<0.001) and lower differentiation grade (RR=1.57, 95% CI=1.29 to 1.90, p<0.001). CKS2 expression levels were not significantly correlated with patients' age (RR=1.11, 95% CI=0.99 to 1.26, p=0.071) or sex (RR=0.98, 95% CI=0.90 to 1.07, p=0.653). An assessment of the articles showed no significant publication bias, confirming the robustness of these findings. The bioinformatic analysis further confirmed CKS2 upregulation in the examined cancer types and its association with poor OS in glioma (HR=1.97, 95% CI=1.78 to 2.18, p=3.70×10-42), liver hepatocellular carcinoma (HR=1.56, 95% CI=1.31 to 1.86, p=3.50×10-7) and lung adenocarcinoma (HR=1.27, 95% CI=1.10 to 1.48, p=1.70×10-3). CONCLUSIONS: Elevated CKS2 expression is associated with poor prognosis in a subset of malignant tumours, highlighting its potential as a prognostic marker. PROSPERO REGISTRATION NUMBER: CRD42023394038.

Radiation and resolve: unlocking the synergistic potential of radioimmunotherapy in advanced lung cancer management.

Plain language summary This editorial talks about combining radiation therapy (using high-energy rays to kill cancer cells) and immunotherapy (boosting the body's immune system to fight cancer) to treat advanced lung cancer. When used together, these therapies can work better to kill more cancer cells and help patients live longer. But, there's still a lot we don't know. For instance, we need to figure out the best timing and doses for these treatments, and which patients will benefit the most. The article stresses that more research is needed to answer these questions and make this combined treatment a more effective option for advanced lung cancer patients.

This editorial talks about combining radiation therapy (using high-energy rays to kill cancer cells) and immunotherapy (boosting the body's immune system to fight cancer) to treat advanced lung cancer. When used together, these therapies can work better to kill more cancer cells and help patients live longer. But, there's still a lot we don't know. For instance, we need to figure out the best timing and doses for these treatments, and which patients will benefit the most. The article stresses that more research is needed to answer these questions and make this combined treatment a more effective option for advanced lung cancer patients.

Nanotechnology and curcumin: a novel and promising approach in digestive cancer therapy.

This study reviews the application of nanotechnology and curcumin, a polyphenol extracted from turmeric, in treating digestive cancers, one of the most common types of malignancies worldwide. Despite curcumin's potential for inhibiting tumor growth, its clinical application is hindered by issues such as poor solubility and bioavailability. Nanomedicine, with its unique ability to enhance drug delivery and reduce toxicity, offers a solution to these limitations. The paper focuses on the development of nanoformulations of curcumin, such as nanoparticles and liposomes, that improve its bioavailability and efficacy in treating digestive cancers, including liver and colorectal cancers. The study serves as a valuable reference for future research and development in this promising therapeutic approach.

This article reviews the burgeoning field of nanotechnology and its applications in anticancer therapeutics, particularly focusing on the utilization of curcumin nanoparticles for the treatment of digestive cancers. With the global rise in the prevalence of digestive cancer, there is an urgent need for newer, more efficient and less toxic therapeutic strategies. Curcumin, a compound derived from turmeric, has shown considerable promise due to its broad-spectrum anticancer properties; however, its clinical application has been limited, as it is not absorbed well by the body and is cleared quickly. Nanotechnology presents a potential solution to these challenges, allowing for the enhanced delivery and therapeutic effectiveness of curcumin. This review delves into the advancements made in the field of curcumin nanoparticle research and the results of preclinical and clinical studies, focusing on digestive cancers. In addition, the challenges encountered in the development and clinical implementation of curcumin nanoparticles are addressed and a perspective on future directions in this promising area of research is provided. By combining the age-old wisdom of curcumin's therapeutic potential with the cutting-edge technology of nanomedicine, this review aims to shed light on the evolution and prospects of a novel therapeutic modality against digestive cancers.

Polyadenosine diphosphate-ribose polymerase inhibitors: advances, implications, and challenges in tumor radiotherapy sensitization.

Polyadenosine diphosphate-ribose polymerase (PARP) is a key modifying enzyme in cells, which participates in single-strand break repair and indirectly affects double-strand break repair. PARP inhibitors have shown great potential in oncotherapy by exploiting DNA damage repair pathways, and several small molecule PARP inhibitors have been approved by the U.S. Food and Drug Administration for treating various tumor types. PARP inhibitors not only have significant antitumor effects but also have some synergistic effects when combined with radiotherapy; therefore they have potential as radiation sensitizers. Here, we reviewed the advances and implications of PARP inhibitors in tumor radiotherapy sensitization. First, we summarized the multiple functions of PARP and the mechanisms by which its inhibitors exert antitumor effects. Next, we discuss the immunomodulatory effects of PARP and its inhibitors in tumors. Then, we described the theoretical basis of using PARP inhibitors in combination with radiotherapy and outlined their importance in oncological radiotherapy. Finally, we reviewed the current challenges in this field and elaborated on the future applications of PARP inhibitors as radiation sensitizers. A comprehensive understanding of the mechanism, optimal dosing, long-term safety, and identification of responsive biomarkers remain key challenges to integrating PARP inhibition into the radiotherapy management of cancer patients. Therefore, extensive research in these areas would facilitate the development of precision radiotherapy using PARP inhibitors to improve patient outcomes.

Metal-organic framework-based photodynamic combined immunotherapy against the distant development of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive, metastatic and apparently drug-resistant subtype of breast cancer with a higher immune response compared to other types of breast cancer. Photodynamic therapy (PDT) has been gaining popularity for its non-invasive nature, minimal side effects, and spatiotemporally controlled benifits. The use of metal-organic frameworks (MOFs) loaded with programmed death-ligand 1 inhibitors (iPD-L1) offers the possibility of combining PDT with immunotherapy. METHOD: Here, we construct PCN-224, a MOFs with good biocompatibility and biodegradability for the delivery of the PD-L1 small molecule inhibitor BMS-202 to achieve a synergistic anti-tumor strategy of PDT and immunotherapy. Hyaluronic acid (HA) modified PEG (HA-PEG) was synthesized for the outer layer modification of the nanocomplex, which prolongs its systemic circulation time. RESULTS: In vitro cellular experiments show that the nanocomplexes irradiated by 660 nm laser has a strong ability to produce singlet oxygen, which effectively induce PDT. PDT with strong immunogenicity leads to tumor necrosis and apoptosis, and induces immunogenic cell death, which causes tumor cells to release danger associated molecular patterns. In combination with iPD-L1, the combination therapy stimulates dendritic cell maturation, promotes T-cell activation and intratumoral infiltration, and reshapes the tumor immune microenvironment to achieve tumor growth inhibition and anti-distant tumor progression. CONCLUSIONS: MOFs-based nano-systems as a platform for combination therapy offer a potentially effective strategy for the treatment of TNBC with high metastatic rates.

Amplifying cancer treatment: advances in tumor immunotherapy and nanoparticle-based hyperthermia.

In the quest for cancer treatment modalities with greater effectiveness, the combination of tumor immunotherapy and nanoparticle-based hyperthermia has emerged as a promising frontier. The present article provides a comprehensive review of recent advances and cutting-edge research in this burgeoning field and examines how these two treatment strategies can be effectively integrated. Tumor immunotherapy, which harnesses the immune system to recognize and attack cancer cells, has shown considerable promise. Concurrently, nanoparticle-based hyperthermia, which utilizes nanotechnology to promote selective cell death by raising the temperature of tumor cells, has emerged as an innovative therapeutic approach. While both strategies have individually shown potential, combination of the two modalities may amplify anti-tumor responses, with improved outcomes and reduced side effects. Key studies illustrating the synergistic effects of these two approaches are highlighted, and current challenges and future prospects in the field are discussed. As we stand on the precipice of a new era in cancer treatment, this review underscores the importance of continued research and collaboration in bringing these innovative treatments from the bench to the bedside.

Involved-field irradiation or elective-nodal irradiation in neoadjuvant chemo-radiotherapy for locally-advanced esophageal cancer: comprehensive analysis for dosimetry, treatment-related complications, impact on lymphocyte, patterns of failure and survival.

Purpose: To compare the differences between involved-field irradiation (IFI) and elective nodal irradiation (ENI) in selecting the optimal target area for neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Materials and methods: We retrospectively analyzed 267 patients with LA-ESCC, of whom 165 underwent ENI and 102 underwent IFI. Dosimetry, treatment-related complications, pathological responses, recurrence/metastasis patterns, and survival were compared between the two groups. Results: The median follow-up duration was 27.9 months. The R0 resection rates in the IFI and ENI groups were 95.1% and 92.7%, respectively (p=0.441), while the pathological complete response (pCR) rates were 42.2% and 34.5%, respectively (p=0.12). The ENI group received higher radiation doses to the heart (HV30:23.9% vs. 18%, p=0.033) and lungs (LV30:7.7% vs. 4.9%, p<0.001) than the IFI group. Consequently, the ENI group showed a higher incidence of grade 2 or higher radiation pneumonitis (30.3% vs. 17.6%, p=0.004) and pericardial effusion (26.7% vs. 11.8%, p=0.021) than the IFI group. Post-operation fistulas were observed in 3 (2.9%) and 17 cases (10.3%) in the IFI and ENI groups, respectively (p=0.026). In the multivariate analysis, smoking, positive lymph node involvement (pN+), and anastomotic fistula were independent predictors of overall survival (OS). The pN+ patients exhibited a greater propensity for recurrence compared to pN- patients, especially in the first year of follow-up (6.67% vs. 0.56%, p=0.003). Conclusion: The ENI group had a higher incidence of radiation-induced adverse events compared to the IFI group, likely due to the higher radiation doses to normal tissues. Considering the similar disease-free survival (DFS) and OS rates in the two groups, IFI may be suitable for nCRT in patients with LA-ESCC, although further prospective studies are warranted.

Lipid-Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy.

In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid-polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.

Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naïve Stage IV PD-L1+ Non-Small Cell Lung Cancer Patients.

PURPOSE: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. CONCLUSIONS: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1-positive, driver gene-negative primary metastatic NSCLC.

Periplocin suppresses the growth of colorectal cancer cells by triggering LGALS3 (galectin 3)-mediated lysophagy.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major clinical challenge. Periplocin, a major bioactive component of the traditional Chinese herb Cortex periplocae, has recently been reported to be a potential anticancer drug. However, the mechanism of action is poorly understood. Here, we show that periplocin exhibits promising anticancer activity against CRC both in vitro and in vivo. Mechanistically, periplocin promotes lysosomal damage and induces apoptosis in CRC cells. Notably, periplocin upregulates LGALS3 (galectin 3) by binding and preventing LGALS3 from Lys210 ubiquitination-mediated proteasomal degradation, leading to the induction of excessive lysophagy and resultant exacerbation of lysosomal damage. Inhibition of LGALS3-mediated lysophagy attenuates periplocin-induced lysosomal damage and growth inhibition in CRC cells, suggesting a critical role of lysophagy in the anticancer effects of periplocin. Taken together, our results reveal a novel link between periplocin and the lysophagy machinery, and indicate periplocin as a potential therapeutic option for the treatment of CRC.Abbreviations: 3-MA: 3-methyladenine; ACACA/ACC1: acetyl-CoA carboxylase alpha; AMPK: adenosine monophosphate-activated protein kinase; AO: Acridine orange; ATG5: autophagy related 5; ATG7: autophagy related 7; CALM: calmodulin; CHX: cycloheximide; CRC: colorectal cancer; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; ESCRT: endosomal sorting complex required for transport; LAMP1: lysosomal associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MKI67/Ki-67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; P2RX4/P2X4: purinergic receptor P2X 4; PARP1/PARP: poly(ADP-ribose) polymerase 1; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TRIM16: tripartite motif containing 16.