Locally advanced head and neck squamous cell carcinoma treatment efficacy and safety: a systematic review and network meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 3% of new cancer cases and 3% of all deaths worldwide. Most HNSCC patients are locally advanced (LA) at diagnosis. The combination of radiotherapy (RT), chemotherapy, targeted therapy, and immunotherapy are the primary LA-HNSCC treatment options. Nevertheless, the choice of optimal LA-HNSCC treatment remains controversial. We systematically searched public databases for LA-HNSCC-related studies and assess treatment effectiveness and safety by assessing the objective response rate (ORR), ≥3 adverse events (AEs), overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), local-region control (LRC), and disease-specific survival (DSS). 126 randomized controlled clinical trials (RCTs) were included in this study. We show that concurrent RT with nimotuzumab or conventional concurrent chemo-radiotherapy (CCRT) had significantly better efficacy and long-term survival without increasing AEs than RT alone. Accelerated fractionated radiotherapy (AFRT) showed better efficiency than conventional fractionated RT, although it had higher AEs. In addition, concurrent cetuximab combined with RT failed to show a significant advantage over RT alone. Trial registration: PROSPERO CRD42022352127.

Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies.

Copper is an indispensable micronutrient for the development and replication of all eukaryotes, and its redox properties are both harmful and beneficial to cells. An imbalance in copper homeostasis is thought to be involved in carcinogenesis. Importantly, cancer cell proliferation, angiogenesis, and metastasis cannot be separated from the effects of copper. Cuproposis is a copper-dependent form of cell death that differs from other existing modalities of regulatory cell death. The role of cuproptosis in the pathogenesis of the nervous and cardiovascular systems has been widely studied; however, its impact on malignant tumors is yet to be fully understood from a clinical perspective. Exploring signaling pathways related to cuproptosis will undoubtedly provide a new perspective for the development of anti-tumor drugs in the future. Here, we systematically review the systemic and cellular metabolic processes of copper and the regulatory mechanisms of cuproptosis in cancer. In addition, we discuss the possibility of targeting copper ion drugs to prolong the survival of cancer patients, with an emphasis on the most representative copper ionophores and chelators. We suggest that attention should be paid to the potential value of copper in the treatment of specific cancers.

Functions and mechanisms of lactylation in carcinogenesis and immunosuppression.

As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor proteins are inert and must be modified posttranslationally to enable a wide range of protein types and functions. Protein posttranslational modifications (PTMs) are well recognized as being directly associated with carcinogenesis and immune modulation and have emerged as important targets for cancer detection and treatment. Lactylation (Kla), a novel PTM associated with cellular metabolism found in a wide range of cells, interacts with both histone and nonhistone proteins. Unlike other epigenetic changes, Kla has been linked to poor tumor prognosis in all current studies. Histone Kla can affect gene expression in tumors and immunological cells, thereby promoting malignancy and immunosuppression. Nonhistone proteins can also regulate tumor progression and treatment resistance through Kla. In this review, we aimed to summarize the role of Kla in the onset and progression of cancers, metabolic reprogramming, immunosuppression, and intestinal flora regulation to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.

Mechanisms and applications of radiation-induced oxidative stress in regulating cancer immunotherapy.

Radiotherapy (RT) is an effective treatment option for cancer patients, which induces the production of reactive oxygen species (ROS) and causes oxidative stress (OS), leading to the death of tumor cells. OS not only causes apoptosis, autophagy and ferroptosis, but also affects tumor immune response. The combination of RT and immunotherapy has revolutionized the management of various cancers. In this process, OS caused by ROS plays a critical role. Specifically, RT-induced ROS can promote the release of tumor-associated antigens (TAAs), regulate the infiltration and differentiation of immune cells, manipulate the expression of immune checkpoints, and change the tumor immune microenvironment (TME). In this review, we briefly summarize several ways in which IR induces tumor cell death and discuss the interrelationship between RT-induced OS and antitumor immunity, with a focus on the interaction of ferroptosis with immunogenic death. We also summarize the potential mechanisms by which ROS regulates immune checkpoint expression, immune cells activity, and differentiation. In addition, we conclude the therapeutic opportunity improving radiotherapy in combination with immunotherapy by regulating OS, which may be beneficial for clinical treatment.

Progress on the molecular mechanism of portal vein tumor thrombosis formation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with poor prognosis and high mortality. Early-stage HCC has no obvious clinical symptoms, and most patients are already at an advanced stage when they are diagnosed. Portal vein tumor thrombus (PVTT) is the most common complication and a poor prognostic factor for HCC, which frequently leads to portal vein hypertension, ascites, gastrointestinal bleeding, and tumor metastasis. The formation of PVTT is related to the complex structure and hemodynamic changes of the portal vein and is closely related to changes at the cellular and molecular levels. The differentially-expressed genes (DEGs) between PVTT and primary tumor (PT) suggest that the two tissues may have different clonal origins. Epigenetic and proteomic analyses also suggest complex and diverse mechanisms for the formation of PVTT. In addition, the tumor microenvironment and energy metabolism pathways are interrelated in regulating the invasion and progression of PVTT. Aerobic glycolysis and the tumor immune microenvironment have been the focus of recent studies on PVTT. In this review, we summarize the mechanism of PVTT formation at the cellular and molecular levels to provide information to guide better prevention and treatment of PVTT in the clinic.

Sulforaphane regulates Nrf2-mediated antioxidant activity and downregulates TGF-ß1/Smad pathways to prevent radiation-induced muscle fibrosis.

AIMS: This study aimed to examine the efficacy of sulforaphane (SFN) in preventing radiation-induced muscle fibrosis (RIMF) and the potential role in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant stress. MAIN METHODS: The RIMF model was established by a single irradiation of the left thigh of C57BL/6 J mice, and the mice were then randomly divided into control, SFN, irradiation (IR), and IR + SFN (IR/SFN) groups. The serum and skeletal muscle were collected eight weeks after irradiation, and changes in oxidative stress and muscle fibrosis were detected. KEY FINDINGS: The IR group showed a more obvious skeletal muscle fiber atrophy, significantly higher number of collagen fibers, and higher inflammatory cell infiltration compared to control group. Compared to the IR group, the IR/SFN group had orderly arranged muscle fibers, decreased collagen fibers, and infiltration of inflammatory cells. In addition, compared with the control group, the expression of oxidative stress-related indexes was significantly increased, accompanied by activation of the transforming growth factor (TGF-ß)/Smad pathway and its downstream fibrogenic molecules in the skeletal muscle of the IR group. After SFN intervention, the above indices were significantly restored. Furthermore, SFN induced the upregulation of Nrf2, activation of AKT, and inhibition of GSK-3ß and Fyn accumulation. SIGNIFICANCE: These results revealed that Nrf2 plays a central role in protecting against RIMF. Furthermore, SFN prevents RIMF by activating Nrf2 via the AKT/GSK-3ß/Fyn pathway.

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer.

Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.

Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism.

Radiotherapy failure and poor tumor prognosis are primarily attributed to radioresistance. Improving the curative effect of radiotherapy and delaying cancer progression have become difficult problems for clinicians. Glucose metabolism has long been regarded as the main metabolic process by which tumor cells meet their bioenergetic and anabolic needs, with the complex interactions between the mitochondria and tumors being ignored. This misconception was not dispelled until the early 2000s; however, the cellular molecules and signaling pathways involved in radioresistance remain incompletely defined. In addition to being a key metabolic site that regulates tumorigenesis, mitochondria can influence the radiation effects of malignancies by controlling redox reactions, participating in oxidative phosphorylation, producing oncometabolites, and triggering apoptosis. Therefore, the mitochondria are promising targets for the development of novel anticancer drugs. In this review, we summarize the internal relationship and related mechanisms between mitochondrial metabolism and cancer radioresistance, thus exploring the possibility of targeting mitochondrial signaling pathways to reverse radiation insensitivity. We suggest that attention should be paid to the potential value of mitochondria in prolonging the survival of cancer patients.

Cooperation effects of radiation and ferroptosis on tumor suppression and radiation injury.

Ferroptosis is a kind of oxidative stress-dependent cell death characterized by iron accumulation and lipid peroxidation. It can work in conjunction with radiation to increase reactive oxygen species (ROS) generation and disrupt the antioxidant system, suppressing tumor progression. Radiation can induce ferroptosis by creating ROS, depleting glutathione, activating genes linked to DNA damage and increasing the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in tumor cells. Furthermore, ferroptosis can enhance radiosensitivity by causing an iron overload, destruction of the antioxidant system, and lipid peroxidation. Radiation can also cause ferroptosis in normal cells, resulting in radiation injury. The role of ferroptosis in radiation-induced lung, intestinal, skin, and hematological injuries have been studied. In this review, we summarize the potential mechanisms linking ferroptosis, oxidative stress and radiation; analyze the function of ferroptosis in tumor suppression and radiation injury; and discuss the potential of ferroptosis regulation to improve radiotherapy efficacy and reduce adverse effects.

ARTS, an unusual septin, regulates tumorigenesis by promoting apoptosis.

Apoptosis plays particularly important roles in tumorigenesis through various mechanisms. Apoptosis can be initiated by both extrinsic and intrinsic signals centered in and coming from the mitochondria. Antiapoptotic proteins promote tumor progression, and the occurrence and progression of tumors are closely related to antiapoptotic protein expression. As the only member of the septin gene family with proapoptotic function, apoptosis-related proteins in the TGF-ß signaling pathway (ARTS) has received extensive attention for its unique structure. In contrast, unlike other known inhibitors of apoptosis protein (IAP) antagonists, ARTS exhibits a stronger tumor suppressor potential. Recent research has shown that ARTS can bind and inhibit XIAP and Bcl-2 directly or assist p53 in the degradation of Bcl-XL. Here, we review recent advances in the molecular mechanisms by which the proapoptotic protein ARTS, with its unique structure, inhibits tumorigenesis. We also discuss the possibility of mimicking ARTS to develop small-molecule drugs.

Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy.

Radiation therapy plays an increasingly important role in cancer treatment. It can inhibit the progression of various cancers through radiation-induced DNA breakage and reactive oxygen species (ROS) overload. Unfortunately, solid tumors, such as breast and lung cancer, often develop a hypoxic microenvironment due to insufficient blood supply and rapid tumor proliferation, thereby affecting the effectiveness of radiation therapy. Restraining hypoxia and improving the curative effect of radiotherapy have become difficult problems. Ferroptosis is a new type of cell death caused by lipid peroxidation due to iron metabolism disorders and ROS accumulation. It plays an important role in both hypoxia and radiotherapy and can enhance the radiosensitivity of hypoxic tumor cells by amplifying oxidative stress or inhibiting antioxidant regulation. In this review, we summarize the internal relationship and related mechanisms between ferroptosis and hypoxia, thus exploring the possibility of inducing ferroptosis to improve the prognosis of hypoxic tumors.