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.

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.

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.

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.

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.

Dendritic cells (DCs) derived extracellular vesicles represent a promising vehicle for the activation of adaptive immunity, demonstrating significant potential in the development of cancer nanovaccines. The aim of this study was to evaluate the antitumor efficacy of a functional DCs-derived extracellular vesicles in castration-resistant prostate cancer.

Colorectal cancer (CRC) is among the most prevalent malignant tumors in the digestive system and is the third leading cause of cancer-related mortality. In recent years, immunotherapy has markedly enhanced the objective response and survival rates for CRC patients. However, the therapeutic efficacy of immunotherapy remains insufficient for the majority of proficient mismatch repair (pMMR) CRC patients, with 20% to 30% of deficient mismatch repair (dMMR) patients demonstrating poor responses or developing drug resistance. Increasing evidence underscores the critical role of intestinal microorganisms in modulating the effectiveness of immunotherapy, particularly in regulating the tumor microenvironment (TME).

There is a continuous increase in the incidence of thyroid cancer. A deeper understanding of the molecular mechanisms of thyroid cancer could significantly improve thyroid cancer management. Newly discovered type of programmed cell death, ferroptosis, has been demonstrated to play a crucial role in many cancers. Mounting evidence shows that there is a close association between ferroptosis and thyroid cancer, which offer a promising therapeutic strategy for thyroid cancer. Ferroptosis is expected to emerge as a novel therapeutic target. Regrettably, the exact role of ferroptosis in thyroid cancer is not yet completely understood. Further, there is currently no summary of ferroptosis in thyroid cancer progression and treatment. Hence, in this review, we aim to revisit the pathological process of thyroid cancer and reveal the role of ferroptosis in thyroid cancer. In addition, we provide evidence that ferroptosis inducers could suppress the growth of thyroid cancer cells. Lastly, we discuss the potential application of ferroptosis inducers in thyroid cancer treatment, as well as possible impediments and corresponding strategies. The relationship between ferroptosis and thyroid cancer will be better understood through this review, which may offer a novel insight into thyroid cancer therapy.

Cadonilimab provides substantial clinical benefits in recurrent or metastatic cervical cancer (R/M CC) in several clinical trials and meeting abstracts. However, the efficacy of cadonilimab in patients with prior failure of anti- programmed death receptor-1 (PD-1) inhibitors, as well as a direct comparison of its efficacy and safety with anti-PD-1 inhibitors, has not been reported in real-world settings.

This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immunotherapy and explore its potential as a conversion treatment for unresectable hepatocellular carcinoma (uHCC).

Immunotherapy-induced pseudomembranous colitis (PMC) is an uncommon but increasingly recognized adverse effect of immune checkpoint inhibitors, particularly in patients with advanced malignancies. We present a case of a 68-year-old male with gastric adenocarcinoma undergoing treatment with immunotherapy and chemotherapy, who developed symptoms of PMC. Workup for Clostridium difficile and other common etiologies was negative. Colonoscopy revealed severe mucosal congestion and yellowish-green exudates, consistent with PMC. Based on the biopsy results and clinical presentation, after excluding common etiologies, immunotherapy-induced PMC was suspected. The patient responded to steroid therapy, with gradual improvement and a tapering regimen upon discharge. This case underscores the diagnostic challenges in identifying the etiology of PMC, particularly when it presents with diffuse involvement of the colon, which is an uncommon presentation for immunotherapy-related colitis. The overlap in clinical, endoscopic, and histopathological findings with other forms of colitis, such as Clostridium difficile infection (CDI) and inflammatory bowel disease, highlights the need for heightened awareness among clinicians. This case highlights the diagnostic challenges in recognizing immunotherapy-induced PMC, particularly with atypical, diffuse colonic involvement. The overlapping features with other colitis make timely diagnosis difficult. Further research is needed to refine diagnostic criteria and management strategies for immunotherapy induced colitis (IMC).

We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC50 values of pro-FTY with those of other drugs. Patient-derived organoids (PDO) were established and utilized for IC50 value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY-treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY-treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast cancer, including multidrug-resistant breast cancer, while avoiding lymphocytopenia, highlighting its clinical potential.

A series of six novel cyanopyridine derivatives bearing a 1,3,4-oxadiazole ring have been synthesized and characterized by FTIR, 13C NMR, 1H NMR, and elemental analysis. DFT calculations were carried out to determine their molecular geometries, electronic properties, and chemical reactivity. Their cytotoxicity has been evaluated against MCF-7 and CaCo-2 human cancer cell lines using the MTT assay. Most compounds displayed poor cytotoxic activity against the MCF-7 cell line except for compound 4e, which showed potent activity with IC50 = 8.352 µM. However, the CaCo-2 cell line was highly sensitive toward most tested compounds with an IC50 range from 2.612 µM to 8.394 µM except for compound 4 d. Molecular docking studies targeting human topoisomerase-IIβ revealed that all compounds exhibited excellent binding affinity within the enzyme's active site, with binding energies ranging from -7.33 to -8.28 kcal/mol. These findings suggest a potential anticancer mechanism underlying the observed cytotoxic activities. All tested compounds revealed low antioxidant activity in the DPPH assay. However, compounds 5b and 5 d presented moderate metal chelating activity. These findings underscore the potential anticancer properties of the synthesized cyanopyridine derivatives.