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Simple Summary: In spontaneous tumor regression, tumors shrink and disappear without conventional treatments. This phenomenon challenges the view that cancer is an irreversible genetic disease and that the only treatment option is to kill cancer cells or surgically remove them. In tumor reversion, cancer cells have been shown to return to normal cells when they are transplanted into a normal cellular environment. Additionally, people consuming a Western diet ingest excessive amounts of dietary phosphate, and a dysregulated oversupply of phosphate can be transported into cells, stimulating the cellular growth that forms tumors. Based on reviewed evidence, this paper proposes that reducing excessive dietary phosphate potentially activates tumor regression and reversion, as components of cancer cells are self-digested. Furthermore, fevers and fasting-mimicking diets are associated with tumor regression, which also may be initiated by reduced phosphate intake. Studies are needed to test dietary phosphate reduction in tumor regression and reversion to improve cancer patient survival. Tumors that spontaneously shrink from unknown causes in tumor regression, and that return to normal cells in tumor reversion, are phenomena with the potential to contribute new knowledge and novel therapies for cancer patient survival. Tumorigenesis is associated with dysregulated phosphate metabolism and an increased transport of phosphate into tumor cells, potentially mediated by phosphate overload from excessive dietary phosphate intake, a significant problem in Western societies. This paper proposes that reduced dietary phosphate overload and reregulated phosphate metabolism may reverse an imbalance of kinases and phosphatases in cell signaling and cellular proliferation, thereby activating autophagy in tumor regression and reversion. Dietary phosphate can also be reduced by sickness-associated anorexia, fasting-mimicking diets, and other diets low in phosphate, all of which have been associated with tumor regression. Tumor reversion has also been demonstrated by transplanting cancer cells into a healthy microenvironment, plausibly associated with normal cellular phosphate concentrations. Evidence also suggests that the sequestration and containment of excessive phosphate within encapsulated tumors is protective in cancer patients, preventing the release of potentially lethal amounts of phosphate into the general circulation. Reducing dietary phosphate overload has the potential to provide a novel, safe, and effective reversion therapy for cancer patients, and further research is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advancements in cancer research have proven immunotherapies to be a promising strategy for the treatment of hematological malignancies. The bispecific antibody (BsAb) format was developed to overcome the issues of monoclonal antibody-based therapies. T-cell engagers (TCEs) are BsAbs, which directly activate T-cells and their anti-tumor features, ultimately resulting in the lysis of the targeted tumor cells. In 2014, the FDA approved blinatumomab for treatment of acute lymphoblastic leukemia. As of November 2023, seven clinically approved TCE therapies are on the market. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: The rising incidence of cancer is a major threat to patients and healthcare services worldwide. It is therefore important to search for novel therapies and new drugs. Honokiol, found in the bark of the magnolia tree, has many properties, including anticancer activity. However, its potential use is limited due to its poor solubility in water. The present study aimed to review the available studies using modern delivery systems for honokiol and determine their anticancer efficacy in vitro and in vivo. Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular mechanisms underlying the observed anticancer effects, emphasizing both in vitro and in vivo studies. The effects of HON application, primarily in the common types of cancers, are presented. Because the therapeutic potential of HON may be limited by its physicochemical properties, appropriate delivery systems are sought to overcome this problem. This review discusses the effect of different nanotechnology-based delivery systems on the efficiency of HON. The data presented show that HON exhibits anticancer effects and can be successfully administered to the site of action. Honokiol exerts its anticancer activity through several mechanisms. Moreover, some authors used the combinations of classical anticancer drugs with HON. Such an approach is very interesting and worth further investigation. Understanding HON's multiple molecular mechanisms would provide valuable insights into how HON might be developed as an effective therapeutic. Therefore, further research is needed to explore its specific applications and optimize its efficacy in diverse cancer types. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of neurogenic locus notch homolog protein 1 (NOTCH1)- and nuclear factor erythroid 2-related factor 2 (NRF2)-related pathways is highly heterogeneous in small cell lung cancer (SCLC) and, when they are both abnormally activated, they can synergistically cause neoplastic proliferation. In this paper, we investigate the possible role of KEAP1 silencing in NRF2 and NOTCH axis deregulation in SCLC by evaluating its impact on the modulation of cellular defense systems, cell growth, and differentiation. We also investigate the impact of these systems' impairment in response to conventional chemotherapies and NOTCH inhibitors in silenced SCLC cell lines with different Kelch-like ECH-associated protein 1 (KEAP1) alterations. The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in the resistance of tumor cells against therapeutic drugs. The dysfunction of the KEAP1/NRF2 system has been correlated with neoplastic patients' outcomes and responses to conventional therapies. In lung tumors, the growth and the progression of cancer cells may also involve the intersection between the molecular NRF2/KEAP1 axis and other pathways, including NOTCH, with implications for antioxidant protection, survival of cancer cells, and drug resistance to therapies. At present, the data concerning the mechanism of aberrant NRF2/NOTCH crosstalk as well as its genetic and epigenetic basis in SCLC are incomplete. To better clarify this point and elucidate the contribution of NRF2/NOTCH crosstalk deregulation in tumorigenesis of SCLC, we investigated genetic and epigenetic dysfunctions of the KEAP1 gene in a subset of SCLC cell lines. Moreover, we assessed its impact on SCLC cells' response to conventional chemotherapies (etoposide, cisplatin, and their combination) and NOTCH inhibitor treatments using DAPT, a γ-secretase inhibitor (GSI). We demonstrated that the KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines and that silencing of KEAP1 by siRNA induced the upregulation of NRF2 with a consequent increase in SCLC cells' chemoresistance under cisplatin and etoposide treatment. Moreover, KEAP1 modulation also interfered with NOTCH1, HES1, and DLL3 transcription. Our preliminary data provide new insights about the downstream effects of KEAP1 dysfunction on NRF2 and NOTCH deregulation in this type of tumor and corroborate the hypothesis of a cooperation of these two pathways in the tumorigenesis of SCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: TP is a widely utilized anticancer medication, particularly effective in treating HCC. Thorough investigation into TP's molecular mechanism in HCC treatment is crucial for precise and combination therapy. In this paper, we have unveiled a novel mechanism of TP in HCC treatment, where it inhibits tumor growth by reducing lipid accumulation. While the inhibition of P53 gene activity is commonly thought to be the reason for TP's effectiveness in treating HCC, this new mechanism serves as a significant complement to the current understanding, paving the way for innovative approaches to HCC treatment. Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease's progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions. [ABSTRACT FROM AUTHOR]

Simple Summary: Colon cancer is a solid tumor that is a prominent contributor to global mortality. Immune cells genetically engineered with a chimeric antigen receptor (CAR) that can recognize cancer-specific targets is a new innovative therapy approach that has had success in treating blood cancers but is still in development for treating solid tumors such as colon cancer. Part of the reason for the added difficulty in targeting solid tumors is the tumor microenvironment that acts as a protective barrier around a solid tumor. In this research paper, we have developed a new cellular approach for the targeted treatment of colon cancer that is designed to overcome the tumor microenvironment. We tested this new CAR cell therapy against multiple solid colon cancer models, and confirmed its efficacy and functionality in finding and eliminating solid tumors. Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach. [ABSTRACT FROM AUTHOR]