Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.

In China, many breast cancer (BC) patients opt for traditional Chinese medicine (TCM) to manage unpleasant symptoms. This study aimed to investigate the symptom clusters among patients with BC who are undergoing endocrine therapy and actively seek TCM treatment in China.

Anti-cancer drugs can be toxic to healthy cells in the body and have the potential to cause irreversible damage to ovarian tissue. This may lead to premature ovarian insufficiency. There are two main strategies to preserve fertility in women undergoing chemotherapy treatment for cancer. One is controlled ovarian hyperstimulation with gonadotropins and a protective agent for safety, followed by freezing of oocytes or embryos; the other is ovarian suppression using gonadotropin-releasing hormone agonists (GnRH agonists). This review aims to gain an understanding of the best way to support women with cancer to preserve their fertility. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.

The expanding clinical utilization of immune checkpoint inhibitors (ICIs) in oncology has brought increasing attention to thyroid dysfunction as a prominent immune-related adverse event (irAE). Elucidating the pathophysiological mechanisms underlying ICI-induced thyroiditis represents a critical step toward developing evidence-based diagnostic protocols and targeted therapeutic interventions for cancer patients undergoing immunotherapy. This comprehensive review systematically examines current advances in understanding the etiopathogenesis of ICI-induced thyroiditis. First, we described pharmacological characterization of ICIs, then discussed multifactorial analysis of cellular and molecular contributors to thyroid autoimmunity following ICI administration and finally analyzed critical evaluation of emerging hypotheses regarding primary pathogenic drivers. Through this review, we aim to establish mechanistic connections between ICI pharmacodynamics and thyroid tissue immunopathology.

Tumor cells can utilize the immune checkpoint pathway to inhibit T cell activation and evade the attack of tumor specific T cells. While immune checkpoint inhibitors (ICIs) competitively bind to checkpoint molecules to block checkpoint mediated suppression of the immune system. Immune checkpoint inhibitors have emerged as a milestone in cancer immunotherapy, demonstrating significant efficacy in various cancers. However, their clinical application still faces challenges such as low response rates (<30% in solid tumors), significant side effects, and suppression by the tumor microenvironment. Nanomaterials offer new solutions to optimize the therapeutic effects of ICIs. This article explores the potential of combining nanomaterials with ICIs in cancer treatment.

Cases with massive (diameter ≥10 cm) hepatocellular carcinomas (HCCs) are uncommon and typically have poor outcomes; however, conversion therapy offers a beacon of hope for remission in patients with massive unresectable HCCs. Recently, immune checkpoint inhibitors (ICIs) have been used in combination with other treatment modalities to improve the response rates to conversion therapies, yet the safety and generalizability of this combination have not been extensively validated. Herein, we report a man with a chief complaint of abdominal pain who was diagnosed with massive unresectable HCC. Notably, the patient successfully underwent curative surgery after quadruple conversion therapy using tislelizumab (an ICI), lenvatinib, transarterial chemoembolization, and hepatic arterial infusion chemotherapy directed by a multidisciplinary team. With a complete response achieved, this case demonstrated the major potential of this combination regimen for HCC, and the remarkable efficacy was also reflected by substantial reductions in both alpha-fetoprotein and des-gamma-carboxy prothrombin overall. Nevertheless, transient increases in both biomarkers (tumor marker pseudoprogression) were observed within the first three weeks after initiating ICI treatment. Furthermore, the patient developed a biliary stricture, which resolved after discontinuing the ICI and was ultimately assessed as an immune-related adverse event. Therefore, in the context of combination therapy, further evaluation of the robustness of tumor markers is warranted, and it is crucial for clinicians to be mindful of potential immune-related adverse events.

Type 1 diabetes (T1D) is an autoimmune-mediated disorder that leads to the destruction of pancreatic beta-cells, insulin deficiency, and chronic hyperglycemia. It is one of the most common childhood endocrine disorders. Recent evidence indicates that aberrant Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling exacerbates T1D by promoting the production of proinflammatory cytokines and chemokines. By blocking JAK-mediated phosphorylation of STAT proteins, JAK inhibitors help alleviate cytokine-driven inflammation, reduce insulin requirements, and relieve complications such as painful peripheral neuropathy, potentially preserving residual beta-cell function and improving glycemic control. Moreover, emerging data underscore the potential synergy between JAK inhibitors and immune checkpoint therapies targeting the programmed cell death protein 1 (PD-1) pathway, as PD-1/Programmed cell death ligand 1 (PD-L1) inhibitors used in antitumor therapy can induce immune checkpoint inhibitor-induced diabetes (CPI-DM). This review examines the impact of JAK inhibitors on beta-cells and immune cells in T1D, along with their safety profiles and adverse effects. It explores the potential benefits and risks of combining JAK inhibitors in the management of CPI-DM associated with anti-PD-1/PD-L1 therapy. In conclusion, while JAK inhibitors have demonstrated the potential to reduce inflammation and preserve beta-cell function in preclinical studies, further clinical trials are needed to confirm their long-term safety and efficacy in patients with T1D and CPI-DM.

Acute myeloid leukemia (AML) is a clonal malignant proliferative disease of myeloid progenitor cells in the hematopoietic system, with a lower than 5-year overall survival rate. At present, three FLT3 inhibitors have been approved, but these drugs are prone to cause resistance after a period of medication. Developing new FLT3 inhibitors with novel structures is an effective strategy to enhance drug treatment efficacy. This study presents an extension of our effort to design and synthesize a series of novel pyrimidine-2,4-diamine derivatives as inhibitors of FLT3. The most active compound, 7r, showed significant inhibition against FLT3 with IC50 value of 7.82 nM. In addition, 7r exhibited prominent anticancer activities against AML cell lines, such as MV4-11 (IC50 = 46.07 nM) and MOLM-13 (IC50 = 51.6 nM). Compound 7r inhibited phosphorylation of FLT3 pathways in a dose-dependent manner in MV4-11 cell lines.

Aurora kinases, AURKA, AURKB, and AURKC, are serine/threonine kinases that play a vital role in regulating cell division and mitosis, particularly in the separation of chromosomes. These kinases are often overexpressed in human tumor cell lines, indicating their potential involvement in tumorigenesis. Preliminary evidence supports the use of Aurora kinase inhibitors for certain types of tumors, several AURKs inhibitors are currently under phase I and II trials. As a result, there is a growing interest in identifying small-molecule Aurora kinase inhibitors to develop as anti-cancer agents. The regulation of the cell cycle, including mitosis, is increasingly recognized as a key target in the fight against various forms of cancer. Novel drugs are being designed to inhibit the function of regulatory proteins, such as Aurora kinases, with the goal of creating personalized treatments. This review summarizes the biology of Aurora kinases in the context of cancer, integrating both preclinical and clinical data. It discusses the challenges and opportunities associated with using Aurora kinases to enhance cancer treatment. Future directions for Aurora kinase-based therapies include developing more selective inhibitors that minimize off-target effects and improve therapeutic efficacy. Researchers are also exploring combination therapies that use Aurora kinase inhibitors alongside other targeted treatments to overcome resistance and improve patient outcomes. Additionally, advancements in biomarker discovery are expected to facilitate the identification of patients most likely to benefit from Aurora kinase-targeted therapies, paving the way for more personalized approaches to cancer treatment.

X-linked inhibitor of apoptosis (XIAP) inhibits caspases 3, 7, and 9, thereby preventing cell apoptosis. Endogenous Second mitochondria-derived activator of caspase (Smac) competes out the binding of caspases with XIAP and causes apoptosis, so that Smac mimetics are under clinical trials for anti-cancer chemotherapy. We demonstrated by selectively alkylating caspase 7 (CASP7) to release the active CASP7 for killing the drug-resistant cancer cells with accumulated XIAP:CASP7 resulted from caspase-3 down-regulation (CASP3/DR). However, finding a reversible inhibitor of the protein-protein interaction (PPI) poses a significant challenge. Here, we identified a reversible XIAP:CASP7 inhibitor, 643943, through a multiple-mode virtual screening strategy. In vitro experiments revealed that 643943 bound to CASP7, released the linker-BIR2 domain of XIAP, and activated the caspase. Removing an essential hydroxyl group on 643943 or replacing the OH-interacting Asp93 on CASP7 caused loss of 643943 cytotoxicity, revealing the binding mode. This compound thus selectively killed MCF-7 and other CASP3/DR triple-negative breast cancer cell lines, but not the cancer and normal cell lines expressing higher levels of CASP3 in vitro and in vivo. Moreover, 643943 overcame chemoresistance via down-regulating β-catenin and its associated ABC transporters in paclitaxel-resistant MCF-7 cells. Our studies not only serve as a proof-of-concept for using XIAP:CASP7 as a drug target, but also provide the first reversible XIAP:CASP7 inhibitor for cancer therapy of CASP3/DR malignancies.

Immunotherapy, including immune checkpoint inhibition, has transformed the prognosis of many patients with cancer. However, most patients have primary or secondary resistant tumors to currently available cancer immunotherapies. Changes in glycosylation of malignant cells and in the tumor microenvironment are a new target to overcome resistance to current cancer immunotherapies and to improve the outcome of patients. Here, we summarize how changes in glycosylation in cancer have functional consequences on the immune system. Such changes can be directly targeted with drugs. Moreover, they can mediate immune-suppressive effects. For example, increased sialylation can enhance interactions with immune-inhibitory Siglec receptors, and galectin-mediated interactions can modulate immune responses in the context of cancer. Finally, we provide an overview of approaches to therapeutically target these changes for the improvement of cancer immunotherapy.

The use of trastuzumab and programmed death-1 (PD-1) inhibitor is effective in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer; however, their use has not been investigated in patients with localized disease. This phase 2 trial evaluates the safety and efficacy of dual PD-1 (sintilimab) and HER2 blockade with chemotherapy in patients with resectable HER2-positive gastric and gastro-esophageal junction adenocarcinoma. 22 patients are enrolled, and 20 patients undergo surgery. The primary endpoint is achieved; 12 (55%, 95% confidence interval [CI]: 32-76) of 22 patients have a major pathological response, and 11 (50%, 95% CI: 28-72) of 22 patients achieve pathological complete response. The most common grade 3 treatment-related adverse events are neutropenia and thrombocytopenia. No treatment-related deaths occur. Transcriptomic analysis, bioinformatics analysis, and immunofluorescence staining demonstrate that regulatory T cells are associated with possibility of drug resistance. This study was registered at the Chinese Clinical Trial Registry (identifier: ChiCTR2200058732).

Lisavanbulin is a prodrug of the microtubule-targeting agent avanbulin. Both avanbulin and lisavanbulin have demonstrated significant antitumor activity in several preclinical tumor models including glioblastoma. Previous human studies demonstrated that 48-h infusions of intravenous lisavanbulin were well tolerated with preliminary activity in recurrent glioblastoma. The current phase 1/2a study evaluates the safety and tolerability of once-daily oral lisavanbulin in patients with solid tumors or recurrent glioblastoma or high-grade glioma. Lisavanbulin is associated with profound, durable responses in a subset of patients with recurrent refractory grade 4 astrocytoma or glioblastoma. We present here the clinical and translational results from this trial, including a description of a response-predictive molecular signature that warrants further exploration in these tumor types of significant unmet need. The study is registered at ClinicalTrials.gov (NCT02490800).

We report a rare case of pericardial tamponade in a 77-year-old male with metastatic squamous cell carcinoma (SCC) of the head and neck receiving pembrolizumab. Despite pembrolizumab revolutionizing cancer treatment, it can engender a spectrum of immune-related adverse events. Our patient presented with acute dyspnea and chest pain two weeks post pembrolizumab infusion and was diagnosed with pericardial tamponade requiring an emergent pericardial window. Our case highlights the importance of recognizing and managing this life threatening cardiac event that occurs in up to 0.4% of patients on pembrolizumab or other immune checkpoint inhibitors (ICI).

The treatment of solid tumors faces substantial hurdles because of inadequate drug delivery and the immunosuppressive tumor microenvironment. To address these challenges, we developed a therapeutic platform using macrophages loaded with ferritin-drug conjugates, referred to as macrophage-drug conjugates (MDC), and applied it to glioblastoma, an immunologically cold solid tumor. MDC loaded with ferritin-conjugated monomethyl auristatin E enabled efficient, cell contact-dependent transfer of the payload by a mechanism involving transfer of iron-binding proteins, from either mouse or human macrophages preferentially into glioma cells. This targeted delivery and therapeutic efficacy was demonstrated across in vitro coculture systems, ex vivo assays using dissociated glioblastoma patient tumor samples, and in vivo using orthotopic glioblastoma mouse models, all while maintaining a favorable preclinical safety profile evidenced by minimal systemic toxicity and localized drug biodistribution. Beyond direct tumor cell killing leading to significant tumor regression and prolonged survival in these models, MDC therapy reprogrammed the immunosuppressive tumor microenvironment. Immune profiling by spectral flow cytometry revealed enhanced infiltration and activation of cytotoxic T lymphocytes and B lymphocytes while reducing immunosuppressive regulatory T cells. This culminated in a robust, durable, T cell-dependent antitumor immune response, the necessity of which was confirmed through studies in immunodeficient mouse models and by lymphocyte depletion, and which conferred protection against tumor rechallenge. The combined cytotoxic and immunomodulatory effects highlight the potential of MDC therapy as a promising strategy for glioblastoma treatment and support its further clinical development.

Researchers screen candidate anti-cancer drugs for their ability to inhibit tumor growth in patient-derived xenografts (PDXs). Typically, a single laboratory will use a single measure of tumor growth.

The present study aimed to evaluate the protective effects of Aloe vera on doxorubicin (DOX)-induced degeneration in ovarian follicles and stromal cells in mice. Mice (n=48) were randomly divided into six groups. The positive control group mice received pretreatment of N-acetylcysteine orally (po), followed by a single intraperitoneal (ip) dose of DOX after 1 h (NAC+DOX). The negative control group mice were pre-treated with saline (po) and administered a single DOX dose (ip) after 1 h (SAL+DOX). The other groups of mice were pre-treated with different concentrations (0.1, 1.0, or 10.0 mg/kg; po) of Aloe vera and then received a single dose of DOX (ip) after 1 h (AV0.1+DOX, AV1.0+DOX, and AV10.0+DOX). The control group received saline po and ip (SAL+SAL). Aloe vera was administered once daily for 3 consecutive days. On the fourth day, the ovaries were processed for histological analysis, immunohistochemistry, and real-time PCR (mRNA for superoxide dismutase (SOD), catalase (CAT), nuclear factor erythroid 2-related factor 2 (NRF2), and tumor necrosis factor-α (TNF-α). Results showed that 0.1 and 1.0 mg/kg Aloe vera protected ovarian follicles and stromal density against DOX-induced degeneration. Furthermore, 0.1 and 1.0 mg/kg Aloe vera reduced TNF-α protein expression and increased NRF2, SOD, and CAT mRNA levels. In conclusion, 0.1 and 1.0 mg/kg Aloe vera had protective effects against DOX-induced degeneration in ovarian follicles and stromal cells in mice.

This study investigated the antiglioblastoma potential of nine synthetic anthraquinone derivatives (SAQDs). SAQDs were tested for their in vitro cytotoxicity against PBMCs and GBM02 cells. For PBMC, SAQDs showed no cytotoxic effects up to 100 µM. Four most promising SAQDs (1, 4, 5, and 9) demonstrated significant activity against GBM02, with selectivity index >4.54 for 1, >1.30 for 4 and 5, and >1.19 for 9. These compounds induced morphological changes, incluing cell rounding, cytoplasmic vacuolation, and membrane rupture, and inhibited cell migration. Due to the pharmacological role of oxidative stress, electrochemical methods were used to compare the reductive and oxidative capacities of the SAQD with their antitumor activity. Considering the reported findings, it is feasible to confirm that some SAQDs have antitumor effects, supporting additional studies of AQ for developing novel anticancer medications. Due to the small number of compounds investigated, it was not possible to observe a relationship between electrochemical and biological data. However, the electrochemical data are new and could be used to prepare other compounds on this line. CV data revealed that the sulfone's electron-withdrawing effect facilitated the reduction. At the same time, the sulfides had shown less positive potential for oxidation waves due to the presence of electron-donating groups.

Liver cancer is a common malignancy in the world, and its incidence and mortality rate are increasing year by year. The disease has a short course and a high mortality rate, posing a serious threat to humanity and health. The objective of this study is to create novel liver-targeted nanoparticles as a potential treatment for liver cancer. The aptamer (APS613-1) modified redox-sensitive norcantharidin solid lipid nanoparticles (Apt-PEG2000-ss-NCTD-SLNs) were prepared by emulsified ultrasonic dispersion method and characterized. The tumor targeting, antitumor effect and safety of the nanoparticles were investigated and evaluated in vitro and in vivo. The particle size of Apt-PEG2000-ss-NCTD-SLNs was 87.95 ± 3.32 nm, and the encapsulation efficiency was about 80.74 ± 2.36%, which had good biocompatibility. The results of in vitro experiments showed that, compared with unmodified solid lipid nanoparticles (NCTD-SLNs), Apt-PEG2000-ss-NCTD-SLNs had better targeting for liver tumor cells, and a stronger ability to inhibit cell proliferation and migration, as well as promote cell apoptosis. The in vivo results revealed that Apt-PEG2000-ss-NCTD-SLNs demonstrated good safety and anti-tumor efficacy, and its mechanism was achieved through the inhibition of cell proliferation and induction of apoptosis. The functionalized nanoparticles modified by aptamer APS613-1 can be used for the liver-targeted delivery of antitumor drugs for the treatment of liver cancer, and Apt-PEG2000-ss-NCTD-SLN is a potential drug for the treatment of liver cancer.

SLFN11, a DNA/RNA helicase implicated in replication stress response, has recently emerged as a pivotal determinant of chemotherapy sensitivity across multiple cancer types. The expression level of SLFN11 in various cancers is significantly positively correlated with the sensitivity of cancer cell DNA damage agents. SLFN11 exerts its chemosensitizing effects by RPA-coated single-stranded DNA (ssDNA) at stressed replication forks at stalled replication forks, thereby potentiating the cytotoxicity of platinum agents, topoisomerase inhibitors, and PARP inhibitors. Its roles in inhibiting ATR translation, mediating p53-independent apoptosis, sensitizing towards IFN-γ and enhancing chromatin accessibility also remain investigational. The down-regulation of SLFN11 expression is associated with epigenetic silencing including promoter methylation, histone deacetylation, and the histone methylation. In this paper, we reviewed the recent progress of SLFN11 as predictive biomarker and therapeutic target in multiple cancers including medulloblastoma, prostate cancer, breast cancer, ovarian cancer, lung cancer, head and neck cancer, esophageal carcinoma, gastric carcinoma and colorectal cancer. We also summarized 10 active clinical trials conducting molecular analyses to assess SLFN11's role. By bridging mechanistic understanding with translational opportunities, this review provides a roadmap for leveraging SLFN11 to overcome chemoresistance and advance precision oncology.