Combination Cancer Therapy Research Articles

Phase 1/2 study of the trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) as monotherapy or combination therapy in gastrointestinal cancers: LIGHTBEAM-02A.

TPS846 Background: There is a significant need for new tolerable and effective therapeutic options for colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC) that can provide survival benefit. TROP2 is expressed broadly in several cancers, including CRC, PDAC, and BTC. Sac-TMT (formerly MK-2870/SKB264) is an ADC consisting of a humanized antihuman TROP2 monoclonal antibody, a linker, and a cytotoxic belotecan–derivative topoisomerase I inhibitor. The nonrandomized, open-label, phase 1/2 LIGHTBEAM-02A study (NCT06428409) is being conducted to examine the safety and efficacy of sac-TMT in gastrointestinal cancers. Methods: Approximately 130 patients will be assigned to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n ≤ 50) must have previously treated locally advanced or metastatic colorectal adenocarcinoma; patients in cohort 2 (PDAC; n ≅ 40) must have previously treated locally advanced or metastatic PDAC; patients in cohort 3 (BTC; n ≅ 40) must have previously treated locally advanced or metastatic BTC. Cohort 1 is included in a dose-escalation phase to determine the recommended phase 2 dose of sac-TMT when used in combination with fluorouracil and leucovorin and an efficacy phase. In the dose-escalation phase, patients will receive sac-TMT 3 mg/kg or 4 mg/kg intravenously (IV) every 2 weeks (Q2W) on days 1 and 15 of each 4-week cycle plus 2400 mg/m 2 fluorouracil IV infused over 46-48 hours Q2W and 400 mg/m 2 leucovorin IV Q2W; in the efficacy phase, patients will receive the recommended phase 2 dose of sac-TMT with the same chemotherapy regimen as the dose-escalation phase. Patients in cohorts 2 and 3 will receive sac-TMT 4 mg/kg IV monotherapy Q2W on days 1 and 15 of each 4-week cycle. The primary objectives are to evaluate safety and tolerability and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival. Enrollment is ongoing. Clinical trial information: NCT06428409 .

Self-assembly of Antisense DNA-Camptothecin Amphiphile into Glutathione-Responsive Nanoparticles for Combination Cancer Therapy.

Recent years have witnessed the rapid growth of combination therapy for the treatment of cancer. Chemo and antisense DNA therapies are two clinically proven and efficient treatment modalities for cancer. However, direct delivery of both chemo and antisense oligonucleotides into the cancerous cells is challenging and hence there is a high demand for the development of new strategies that permit the direct delivery of chemo and antisense therapeutic agents in a targeted fashion. Herein, we show a supramolecular approach for the direct delivery of hydrophobic chemo drug and cell impermeable antisense oligonucleotide into a cancer cell in a targeted fashion. Synthesis of an amphiphile (DNA1-CPT) consist of hydrophobic camptothecin (CPT) conjugated to an antisense oligonucleotide (DNA1) via glutathione-responsive disulphide linker is reported. Self-assembly of DNA1-CPT results in the formation of GSH-responsive NPs with CPT as the hydrophobic core and DNA1 as the hydrophilic shell. Self-assembled NPs exhibits excellent cellular internalization via endocytosis pathway, and the high concentration of glutathione inside the cancer cells causes the cleavage of disulphide bond of the NPs and trigger the simultaneous release of CPT and DNA1a. Enhanced cytotoxicity is observed for the NPs due to the synergetic combination of chemo and antisense DNA therapies.

Biomimetic Nanoplatform-Mediated Protective Autophagy Blockage Enhancing Sonodynamic and Ca2+-Overload Combined Therapy for Colon Cancer.

The application of a multimodal combination therapy based on a targeted nanodelivery system has been demonstrated to be more valuable in the treatment of cancer. In this work, a hollow polydopamine delivery system (CCC@HP@M) was designed to achieve sonodynamic and calcium-overload combined therapy for colon cancer. The CCC@HP@M exhibits both homologous tumour-targeting ability and pH-responsive drug release properties, enabling the simultaneous targeted delivery of CaO2 nanoparticles/sonosensitizer Ce6/autophagy inhibitor CQ. The CaO2 nanoparticles as calcium agents capable of triggering Ca2+ overload in tumor cells. The oxidative stress produced by sonodynamic therapy is facilitated by the disruption of calcium homeostasis to enhance the effect of Ca2+ overload-induced apoptosis. Furthermore, the O2 produced by CaO2 augments the sensitization of sonodynamic therapy. The autophagy inhibitor CQ can inhibit protective cellular autophagy, which is activated by sonodynamic therapy and Ca2+ overload. Consequently, autophagy blockage can ensure the therapeutic effect of sonodynamic and Ca2+-overload combined therapy for colon cancer. The results of experiments in vitro and in vivo demonstrate that the stimulus-responsive targeted delivery system achieves autophagy blockage augmented sonodynamic and Ca2+-overload combined therapy of colon cancer. This work offers a promising theoretical basis for optimizing combined treatment strategies for tumors and clinical translational applications.

Angelicin Inhibits NSCLC Tumor Growth via the Inhibition of Cancer-Associated Fibroblasts.

This study aimed to investigate the effect of angelicin on the NSCLC tumor growth. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) play an important role in tumor progression and metastasis, making CAFs an increasingly attractive target for therapeutic intervention. Targeted therapies against CAFs have been considered to have the potential to significantly improve cancer treatment outcomes, overcome resistance, and improve immune evasion. Angelicin (Ang), an active ingredient isolated from the Chinese herbal medicine Psoralea corylifolia Linn., has been reported to inhibit tumor progression. Due to its natural origin, angelicin has good clinical safety and low toxicity. Further clinical studies and exploration of its role as a CAF inhibitor in difficult-to-treat tumors like as NSCLC are expected to offer up a new channel for cancer treatment. Furthermore, angelicin's low cost and good biocompatibility make it have important application potential in cancer combination therapy, especially when used in combination with traditional therapies such as chemotherapy and immunotherapy, which may significantly improve treatment outcomes and reduce side effects. However, the mechanism of its anti-tumor effect remains poorly defined. The aim of this study was to investigate whether ANG modulates CAF activity to inhibit NSCLC progression. NIH3T3 cells are a mouse fibroblast cell line, and the use of NIH3T3 cells as a model for CAFs is mainly due to their natural fibroblast phenotype, ease of culture, good response to stimuli, and ability to simulate the functions of fibroblasts in the tumor microenvironment. NIH3T3 was treated with TGF-β (4ug/ml) and H2O2 (10μM). A conditioned medium was used to study the effect of Ang on tumor growth, invasion, and migration by regulating CAFs.Ang concentrations were set at 12.5, 25, and 50μM for cell cycle experiments and 0, 20, and 40μM for cell migration and invasion experiments. Subcutaneous tumors were established by mixing LLC and NIH3T3 cells to observe the effect of Ang on tumor progression and microenvironment. Fibroblast activity during Ang intervention was monitored by fluorescence-labeled FAPI-04 and 18F-labeled FAPI-04. The molecular pharmacological mechanism of Ang was investigated by RNA sequencing and network pharmacology. The result showed that Ang significantly inhibited TGF-β and H2O2-induced NIH3T3 transformation, as evidenced by reduced expression of markers such as FAPα and α-SMA. Ang inhibited proliferation, invasion and migration of LLC cells induced by CAFs-conditioned medium. In vivo Experiments showed that Ang greatly inhibited tumor growth in Lewis's lung cancer caused by CAFs. Molecular pharmacological analysis showed that Ang could modulate CAFs activity through multiple targets. These data indicate that Ang has a great potential to reduce CAF activity, interfere with the tumor microenvironment, and inhibit tumor growth. However, these findings still need to be further validated, especially considering the heterogeneity of CAFs, the differences between in vitro and in vivo models, and potential side effects. Ang reduced the growth, invasion, and migration of lung cancer by inactive CAFs. This provides a rationale for tumor microenvironment-based treatment of lung cancer and clinical translation of Ang. As a potential anti-cancer drug, Ang has shown significant effects in inhibiting cancer-related fibroblasts (CAFs) and disrupting the tumor microenvironment. However, there are still challenges in translating these findings into clinical treatments, such as heterogeneity of the tumor microenvironment, differences in patient responses, and side effects. Therefore, future research should focus on exploring personalized treatment strategies, evaluating the clinical safety and effectiveness of the drug, and delving deeper into the molecular mechanisms and target sites of Ang.

Hyaluronic acid modified metal-organic frameworks loading cisplatin achieve combined chemodynamic therapy and chemotherapy for lung cancer.

As one of the most commonly used chemotherapeutic agents in clinical practice, cisplatin is unable to selectively accumulate in tumor tissue due to its lack of targeting ability, leading to increased systemic toxicities. Additionally, the effectiveness of monotherapy is greatly limited. Therefore, the development of new cisplatin-based drug delivery systems is essential to improve the effectiveness of tumor treatment. In this study, an iron-based metal-organic framework (MOF) was synthesized to encapsulate cisplatin, and then coated with hyaluronic acid (HA) to create a MOF-based nanoplatform called MPt@HA NPs. This novel nanoplatform achieved the combination of chemodynamic therapy (CDT) with targeted chemotherapy for the treatment of lung cancer. The results showed that MPt@HA NPs have stronger cytotoxicity compared to conventional doses of cisplatin due to the generation of reactive oxygen species (ROS) through the Fenton reaction and DNA damage caused by cisplatin. Therefore, MPt@HA NPs effectively inhibit the tumor growth and prolong the median survival of tumor-bearing mice. Therefore, the MOF-based nanoplatform MPt@HA NPs may present a new option for multi-modal therapy of solid tumors.

Chondroitin sulfate-based dissolvable microneedles loaded with NIR-II photothermal and natural anticancer agents for synergistic melanoma therapy.

Melanoma is characterized by its aggressiveness, high metastatic potential, and numerous mutations, which limit the effectiveness of current treatments. To address this issue, we developed a dissolvable microneedle (MN) system composed of poly(2-ethyl-2-oxazoline) (PEtOz) and chondroitin sulfate (CS). This MN system was loaded with liposomes containing both a NIR-II photothermal small molecule (IRLy) and the natural anticancer agent Gambogic acid (GA), forming Lip(IRLy+GA) MNs. The integration of the dissolvable microneedle with drug-loaded liposomes aligns with the mechanical properties and skin penetration efficiency required for effective drug delivery. It enables minimally invasive, painless, and precise administration of IRLy and GA. Under NIR-II 1064nm laser irradiation, Lip(IRLy+GA) effectively inhibited melanoma by disrupting blood vessels, inducing apoptosis, and altering mitochondrial membrane potential. In a subcutaneous melanoma (A375) model in nude mice, the combination of Lip(IRLy+GA) and laser treatment demonstrated a synergistic effect, enhancing both photothermal and chemotherapeutic outcomes. This research presents a promising strategy that combines NIR-II photothermal agents with natural chemotherapeutic drugs and highlights the potential of microneedles in combination therapies for superficial skin cancers like melanoma.

Metabolomics insights into doxorubicin and 5-fluorouracil combination therapy in triple-negative breast cancer: a xenograft mouse model study.

Breast cancer is one of the most prevalent malignancies and a leading cause of death among women worldwide. Among its subtypes, triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive behavior and limited treatment options. This study aimed to investigate the effects of doxorubicin (DOX) and 5-fluorouracil (5-FU) as monotherapies and in combination using an established MDA-MB-231 xenograft model in female BALB/C nude mice employing advanced metabolomics analysis to identify molecular alterations induced by these treatments. We conducted comprehensive plasma and tumor tissue sample profiling using ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). Each treatment group exhibited unique metabolic profiles in plasma and tumor analysis. Univariate and enrichment analyses identified alterations in metabolic pathways. The combination treatment of DOX + 5-FU induced the most extensive metabolic alterations disrupting key pathways including purine, pyrimidine, beta-alanine, and sphingolipid metabolism. It significantly reduced critical metabolites such as guanine, xanthine, inosine, L-fucose, and sphinganine, demonstrating enhanced cytotoxic effects compared to individual treatments. The DOX treatment uniquely increased ornithine levels, while 5-FU altered sphingolipid metabolism, promoting apoptosis. This in vivo study highlights TNBC's metabolic alterations to chemotherapeutics, identifying potential biomarkers like L-fucose and beta-alanine, and provides insights for improving treatment strategies.

SRC enhanced cisplatin resistance in bladder cancer by reprogramming glycolysis and pentose phosphate pathway

The development of cisplatin resistance often results in a grim prognosis in advanced or recurrent bladder cancer. However, effective treatment strategies for cisplatin resistance have not been well established. Herein, we found that overactivation of SRC is associated with cisplatin-resistance. SRC activates hexokinase2 which up-regulates glycolysis and especially the pentose phosphate pathway that leading to increased nucleotide synthesis and NADPH production which can neutralize reactive oxygen species (ROS) induced by cisplatin, thereby protecting bladder cancer cells from cisplatin-induced DNA damage. This phenomenon was effectively reversed by knockout of SRC and inhibition of SRC activity by the SRC inhibitor, eCF506. Moreover, we constructed Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) from cisplatin-resistant bladder cancer patient. eCF506 exhibited excellent anti-tumor effects and effectively enhanced cisplatin-sensitivity. Altogether, our findings demonstrate that targeting SRC is a promising approach to overcome cisplatin-resistance in bladder cancer, and providing new insights for combination therapy in bladder cancer.

A DNA origami-based enzymatic cascade nanoreactor for chemodynamic cancer therapy and activation of antitumor immunity.

Chemodynamic therapy (CDT) is a promising and potent therapeutic strategy for the treatment of cancer. We developed a DNA origami-based enzymatic cascade nanoreactor (DOECN) containing spatially well-organized Au nanoparticles and ferric oxide (Fe2O3) nanoclusters for targeted delivery and inhibition of tumor cell growth. The DOECN can synergistically promote the generation of hydrogen peroxide (H2O2), consumption of glutathione, and creation of an acidic environment, thereby amplifying the Fenton-type reaction and producing abundant reactive oxygen species, such as hydroxyl radicals (•OH), for augmenting the CDT outcome. The DOECN is decorated with targeting groups to achieve efficient cellular uptake and efficiently induce tumor cell apoptosis, ferroptosis, and immunogenetic cell death, thus realizing potent anticancer therapeutic effects. Intravenous injection of the DOECN effectively promoted the maturation of dendritic cells, triggered adaptive T cell responses, and suppressed tumor growth in a murine cancer model. The DOECN provides a programmable platform for the integration of multiple therapeutic components, showing great potential for combined cancer therapy.

Advances in Pure Drug Self-Assembled Nanosystems: A Novel Strategy for Combined Cancer Therapy.

Nanoparticle-based drug delivery systems hold great promise for improving the effectiveness of anti-tumor therapies. However, their clinical translation remains hindered by several significant challenges, including intricate preparation processes, limited drug loading capacity, and concerns regarding potential toxicity. In this context, pure drug-assembled nanosystems (PDANSs) have emerged as a promising alternative, attracting extensive research interest due to their simple preparation methods, high drug loading efficiency, and suitability for large-scale industrial production. This innovative approach presents new opportunities to enhance both the safety and therapeutic efficacy of cancer treatments. This review comprehensively explores recent progress in the application of PDANSs for cancer therapy. It begins by detailing the self-assembly mechanisms and fundamental principles underlying PDANS formation. The discussion then advances to strategies for assembling single pure drug nanoparticles, as well as the co-assembly of multiple drugs. Subsequently, the review addresses the therapeutic potential of PDANSs in combination treatment modalities, encompassing diagnostic and therapeutic applications. These include combinations of chemotherapeutic agents, phototherapeutic approaches, the integration of chemotherapy with phototherapy, and the synergistic use of immunotherapy with other treatment methods. Finally, the review highlights the potential of PDANSs in advancing tumor therapy and their prospects for clinical application, providing key insights for future research aimed at optimizing this technology and broadening its utility in cancer treatment.

Biodegradable semiconducting polymer nanoparticles for phototheranostics.

Semiconducting polymer nanoparticles (SPNs) have been widely applied for phototheranostics. However, the disadvantage of in vivo long-term metabolism greatly suppresses the clinical application of SPNs. To improve the metabolic rate and minimize the long-term toxicity of SPNs, biodegradable semiconducting polymers (BSPs), whose backbones may be degraded under certain conditions, have been designed. This review summarizes recent advances in BSP-constructed nanoparticles (BSPNs) for phototheranostics. BSPs are divided into two categories: conjugated backbone degradable BSPs (CBD-BSPs) and non-conjugated backbone degradable BSPs (NCBD-BSPs), based on the feature of chemical structure. The biological applications, including cancer imaging and combination therapy, of these BSPNs are described. Finally, the conclusion and future perspectives of this field are discussed.

Tumor microenvironment-regulated nanoplatform for enhanced chemotherapy, cuproptosis and nonferrous ferroptosis combined cancer therapy.

Therapeutic approaches combining various treatments have attracted intensive interests for tumor therapy. Nevertheless, these strategies still face many obstacles, such as overexpressed GSH and hypoxia, owing to the intricate tumor microenvironment (TME). Herein, a versatile nanoplatform, CeO2@CuO2@DOX-RSL3@HA (CCDRH), was initially constructed for promoting the antitumor efficiency via regulation of the TME. The CCDRH was prepared taking mixed valence CeO2 as the nanocarrier, followed by the attachment of CuO2 nanodots, DOX and RSL3 and the camouflaging of hyaluronic acid. The CuO2 could disassemble in the acidic TME to release Cu2+ and H2O2. The POD- and CAT-mimicking activities of CeO2 could convert H2O2 to ˙OH and O2, leading to the enhancement of chemo-chemodynamic therapy. Meanwhile, RSL3 could effectively suppress GPX4 expression, and the overloaded Cu2+ and Ce4+ could deplete excess GSH, resulting in an intensive accumulation of LPO and significant nonferrous ferroptosis. Additionally, Cu+ induces the oligomerization of lipoylated DLAT and downregulates iron-sulfur cluster proteins, resulting in potent cellular cuproptosis. The experimental results revealed that CCDRH exhibited high performance in tumor inhibition, which is attributed to the combined effect of enhanced chemotherapy, ferroptosis and cuproptosis. The study provides a new approach for improving anticancer efficiency via regulation of the TME.

Lipid droplet formation induced by icaritin derivative IC2 promotes a combination strategy for cancer therapy

BackgroundLipid metabolism is crucial in cancer progression. Lipid droplets (LDs) generated in cancer cells can act as protective mechanisms through alleviating lipotoxicity under stress conditions. We previously developed IC2 from the Chinese medicine icaritin as an inhibitor of stearoyl-CoA desaturase 1 (SCD1). IC2 has been shown to disrupt lipid metabolism and inhibits cancer cell proliferation. However, the impact of IC2 on intracellular LDs and the potential of targeting LD formation for combination cancer therapy remain unexplored.MethodsLD formation in cancer cells was analyzed with oil red O or BODIPY staining by microscopy. LD quantification was normalized to the cell number. IC2-induced cellular responses were revealed by transcriptional analysis, real-time PCR, and immunoblotting. Mitochondrial functions were assessed by measuring ATP production and oxygen consumption. The lipid source for LD formation was studied using lipid transporter inhibitors or lipid deprivation. The effect of inhibiting LD formation on IC2's anti-tumor effects was evaluated using MTT assays and apoptosis assays, which was subsequently validated in an in vivo xenografted tumor model.ResultsIC2 exerted anti-tumor effects, resulting in LD formation in various cancer cells. LD formation stimulated by IC2 was independent of extracellular lipid sources and did not result from increased de novo fatty acid (FA) synthesis within the cancer cells. Transcriptional analysis indicated that IC2 disturbed mitochondrial functions, which was confirmed by impaired mitochondrial membrane potential (MMP) and reduced capacity for ATP production and oxygen consumption. Moreover, IC2 treatment led to a greater accumulation of lipids in LDs outside the mitochondria compared with the control group. IC2 inhibited the proliferation of PC3 cells and promoted the apoptosis of the cancer cells. These effects were further enhanced after inhibiting the diacylglycerol acyltransferase 1 (DGAT1), a key intracellular enzyme involved in LD formation. In PC3-xenografted mice, the DGAT1 inhibitor augmented the IC2-induced reduction in tumor growth by modulating LD formation.ConclusionLD formation is a feedback response to IC2’s anti-tumor effects, which compromises the anti-tumor actions. IC2’s anti-tumor efficacy can be enhanced by combining it with inhibitors targeting LD formation. This strategy may be extended to other anti-tumor agents that regulate lipid metabolism.

MTOR Inhibitor Everolimus Modulates Tumor Growth in Small-Cell Carcinoma of the Ovary, Hypercalcemic Type and Augments the Drug Sensitivity of Cancer Cells to Cisplatin.

Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive cancer with a poor prognosis and limited treatment options. Current chemotherapy regimens are predominantly platinum-based; however, the development of platinum resistance during treatment significantly worsens patient outcomes. Everolimus, an mTOR inhibitor, has been widely used in combination cancer therapies and has successfully enhanced the efficacy of platinum-based treatments. Method: In this study, we investigated the combined effects of everolimus and cisplatin on SCCOHT through both in vitro and in vivo experiments, complemented by RNA sequencing (RNA-seq) analyses to further elucidate the therapeutic impact. Result: Our findings revealed that everolimus significantly inhibits the proliferation of SCCOHT cells, induces cell cycle arrest, and accelerates apoptosis. When combined with cisplatin, everolimus notably enhances the therapeutic efficacy without increasing the toxicity typically associated with platinum-based drugs. RNA-seq analysis uncovered alterations in the expression of apoptosis-related genes, suggesting that the underlying mechanism involves autophagy regulation. Conclusions: Despite the current challenges in treating SCCOHT and the suboptimal efficacy of platinum-based therapies, the addition of everolimus significantly suppresses tumor growth. This indicates that everolimus enhances cisplatin efficacy by disrupting survival-promoting signaling cascades and inducing cell cycle arrest. Furthermore, it points to potential biomarkers for predicting therapeutic response.

CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers.

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation, and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target. However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket. Here, we demonstrate that the potent abrogation of MYC gene transcription by CBL0137 induces immunogenic cell death and reduces proliferation in MYC-high but not in MYC-low TNBC in vitro. CBL0137 also significantly inhibited the in vivo growth of primary tumors in a human MYC-high TNBC xenograft model (MDA-MB-231). Moreover, CBL0137 inhibited the tumor growth of highly aggressive mouse 4T1.2 syngeneic TNBC model in immunocompetent mice by inhibiting the MYC pathway and inducing Type I interferon responses. Immune profiling of CBL0137-treated mice revealed significantly enhanced tumor-specific immune responses and increased proportions of tumor infiltrating effector CD8+ T cells, CD4+ T cells, and NK cells. CBL0137-induced immune activation also resulted in increased exhaustion of immune effector cells. In particular, NKG2A up-regulation on activated effector cells and of its ligand Qa-1b on tumors in vivo was identified as a possible immune evasive mechanism. Indeed, NKG2A blockade synergized with CBL0137 significantly inhibiting the in vivo growth of 4T1.2 tumors. Collectively, our findings provide the rationale supporting the exploitation of CBL0137-induced anti-tumor immunity in combination with NKG2A blockade to improve the treatment of TNBC expressing high levels of MYC.

Revisiting hydrogen peroxide as radiosensitizer for solid tumor cells.

Tumor hypoxia is the principal cause of clinical radioresistance. Despite its established role as radiosensitizer, hydrogen peroxide (H2O2) encounters clinical limitations due to stability and toxicity concerns. Recent advancements in drug delivery combine H2O2 with sodium hyaluronate (SH), enabling intratumoral administration of H2O2. This study investigates the radiomodulatory pathways of Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC) (H2O2+SH) under hypoxia. CT26 and 4T1 tumor cells were exposed to H2O2, SH and KORTUC under hypoxic conditions. Toxicity levels were determined using MTT and live-cell analysis. KORTUC's radiomodulatory properties were evaluated by colony formation assay and in spheroids. Reactive oxygen species (ROS) levels, DNA damage, apoptosis and ferroptosis were analyzed using flow cytometry. Oxygen consumption rate (OCR) and mitochondrial complex activity were assessed by Seahorse Analyzer. Oxygen levels were investigated using fiber-optic sensors. The in vitro findings were validated in CT26-bearing mice. KORTUC demonstrated less cytotoxicity than H2O2-alone. KORTUC radiosensitized hypoxic tumor cells in a dose-dependent manner with enhancement ratios of 3.1 (CT26) and 2.7 (4T1). Dose-dependent OCR reduction following KORTUC exposure correlated with complex I and II inhibition, accompanied by mitochondrial ROS elevation. KORTUC injection into a 2D hypoxic tumor model surged O2 levels. KORTUC radiosensitized CT26-tumors, delaying growth by 14days. SH in KORTUC mitigates H2O2 cytotoxicity. We demonstrate that KORTUC overcomes hypoxia-induced radioresistance through inhibition of OCR, via complex I- and II-blockade, leading to tumor reoxygenation. Understanding KORTUC's pathways is essential for developing effective cancer combination therapies.

Hyperthermia Potentiates the Effectiveness of Anticancer Drugs-Cisplatin and Tamoxifen on Ovarian Cancer Cells In Vitro.

Ovarian cancer is one of the most prevalent cancers among women. Due to the frequent problems during treatment, such as relapses or the development of resistance to treatment, new methods of treating this disease are being sought. A special attention is directed towards the combination therapies combining several different anticancer agents. The aim of the following study was to examine the effect of combination therapy with mild hyperthermia (temperatures of 39 °C and 40 °C) and anticancer drugs-cisplatin and tamoxifen-on the SKOV-3 ovarian cancer cell line in vitro. Furthermore, the study also assessed the effect of moderate hyperthermia on the anticancer effectiveness of both of these drugs. The cytotoxic effect of the therapy was assessed using MTT assay and fluorescent acridine orange staining. Changes in the expression of genes involved in apoptosis processes were evaluated using RT-qPCR. It has been shown that the use of combination therapy leads to a significant increase in apoptosis processes in SKOV-3 ovarian cancer cells and, consequently, to a decrease in their viability. At the molecular level, mild hyperthermia leads primarily to a decrease in the expression of anti-apoptotic genes, and also, to a small extent, to an increase in the expression of proapoptotic genes. The results also indicate that moderate hyperthermia has a positive effect on the cytotoxic efficacy of both cisplatin and tamoxifen on ovarian cancer cells. This suggests that hyperthermia could be a potential component in combination therapy for ovarian cancer.

Salmonella-based therapeutic strategies: improving tumor microenvironment and bringing new hope for cancer immunotherapy.

Immunotherapy has revolutionized cancer treatment, yet its effectiveness is limited by immunosuppressive tumor microenvironment (TME). To overcome this challenge, innovative strategies to effectively modulate the TME are urgently needed. Over the past decades, bacteria-mediated cancer immunotherapy has recaptured increasing attention, driven by advances in synthetic biology, genetic engineering and our knowledge of host-pathogen interactions. Among various bacterial species, Salmonella has emerged as a leading candidate with significant therapeutic potential due to its broad-spectrum anti-tumor activity, tumor-targeting ability, immunomodulatory effects, oncolytic properties, genetic programmability, and engineering flexibility. These characteristics enable Salmonella to reshape the immunosuppressive TME, thereby enhancing anti-tumor efficacy. This review elaborates the regulatory effects of Salmonella on key components of the TME, the versatile engineering strategies for optimizing Salmonella's ability to modulate the TME, and recent advancements in combination cancer therapies. We also summarize current clinical applications and discuss challenges of developing safer and more effective Salmonella-based cancer immunotherapy.

Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.

PLK1 inhibitors are emerging anticancer agents that are being tested as monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models has shown potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine the sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, whereas sensitive cells undergo apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that nonselective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their antiproliferative and pro-inflammatory effects via PLK1 inhibition. Specific inhibition of RSK, on the other hand, is anti-inflammatory and promotes a program of antigen presentation. This study reveals the overlooked effects of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve the response to targeted therapies.

YAP/TAZ Inhibitor-Based Drug Delivery System for Selective Tumor Accumulation and Cancer Combination Therapy.

The YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two important transcriptional coactivators that are often aberrantly activated in cancer cells. Their dysregulation promotes cancer development and can confer resistance to anticancer therapies. Therefore, the pharmacological inhibition of YAP/TAZ presents a promising approach for treating tumors with heightened YAP/TAZ activity. However, the clinical use of a known YAP/TAZ inhibitor, niflumic acid (NA), is limited by its poor in vivo half-life. To improve its bioavailability, we developed a series of NA-based prodrug polymers and investigated the impact of NA monomer units on the physicochemical properties of their self-assembled nanoparticles. The optimal pNA polymer was selected as a prodrug micellar nanocarrier to load hydrophobic receptor tyrosine kinase inhibitors (RTKIs) for combination therapy. The nanocarrier selectively accumulated in the tumor and synergistically inhibited tumor growth with the cargo RTKIs, particularly Dasatinib, introducing a nanocombination therapy enhanced breast cancer treatment.