Conditions In Tumor Microenvironment Research Articles

Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

High level of C (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

Estimating Impacts of p16 Status on Tumor Radiosensitivity in Head and Neck Cancer using Predictive Models.

The intrinsic radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) were reported to be able to predict the surviving fraction at 2 Gy and therapeutic effect when delivering actual treatment doses using the gene expression profiles of clinical cases. Given the impact of p16 status, a surrogate marker of the human papillomavirus (HPV) infection, on radiosensitivity, we attempted to apply the RSI and GARD to estimate p16-associated radiosensitivity in head and neck squamous cell carcinoma (HNSC). For this purpose, The Cancer Genome Atlas (TCGA) dataset was employed. In the GARD calculation, we assumed that p16-positive patients received 60 Gy in 30 fractions, while p16-negative patients received 70 Gy in 35 fractions. p16 positivity was associated with favorable characteristics compared to negative patients. The RSI and GARD analyses demonstrated increased radiosensitivity and high therapeutic effect in p16-positive patients, compared to p16-negative patients. Additionally, tumor microenvironmental conditions predicted by other models were also significantly affected by p16 status. Collectively, the models used in this study could be a promising tool for estimating p16-associated radiosensitivity in HNSC.

Stimuli Responsive Molecular Exchange of Structure Directing Agents on Gold Nanobipyramids: Cancer Cell Detection and Synergistic Therapeutics.

Surface-engineered gold nanoparticles have been considered as versatile systems for theranostics applications. Moreover, surface covering or stabilizing agents on gold nanoparticles especially gold nanobipyramids (AuNBPs) provides an extra space for cargo molecules entrapment. However, it is not well studied yet and also the preparation of AuNBPs still remains dependent largely on cetyltrimethylammonium bromide (CTAB), a cytotoxic surfactant. Therefore, the direct use of CTAB stabilized nanoparticles is not recommended for cancer theranostics applications. Herein, we address an approach of dodecyl ethyl dimethylammonium bromide (DMAB) as biocompatible structure directing agent for AuNBPs, which also accommodate anticancer drug doxorubicin (45%), an additional chemotherapeutics agent. Upon near-infrared light (NIR, 808 nm) exposure, engineered AuNBPs exhibit (i) better phototransduction (51 °C) due to NIR absorption ability (650-900 nm), (ii) photo triggered drug release (more than 80%), and (iii) synergistic chemophototherapy for breast cancer cells. Drug release response has been evaluated in tumor microenvironment conditions (84% in acidic pH and 80% at high GSH) due to protonation and high affinity of thiol binding with AuNBPs followed by DMAB replacement. Intracellular glutathione (GSH, 5-7.5 mM) replaces DMAB from AuNBPs, which cause easy aggregation of nanoparticles as corroborated by colorimetric shifts, suggesting their utilization as a molecular sensing probe of early stage cancer biomarkers. Our optimized recipe yield is monodisperse DMAB-AuNBPs with ∼90% purity even at large scales (500 mL volume per batch). DMAB-AuNBPs show better cell viability (more than 90%) across all concentrations (5-500 ug/mL) when directly compared to CTAB-AuNBPs (less than 10%). Our findings show the potential of DMAB-AuNBPs for early stage cancer detection and theranostics applications.

Enhancing Magnetic Hyperthermia Efficacy through Targeted Heat Shock Protein 90 Inhibition: Unveiling Immune-Mediated Therapeutic Synergy in Glioma Treatment.

The induction of heat stress response (HSR) mediated by the generation of heat shock proteins (HSPs) on exposure to magnetic hyperthermia-mediated cancer therapy (MHCT) decreases the efficacy of localized heat treatment at the tumor site, and thus therapy remains a significant challenge. Hence, the present study examined differential HSR elicited in glioma cells post-MHCT under different tumor microenvironment conditions (2D monolayers, 3D monoculture, and coculture spheroids) to recognize target genes that, when downregulated, could enhance the therapeutic effect of MHCT. Gene expression analysis following MHCT revealed that HSP90 was upregulated as compared to HSP70. Hence, to enhance the efficacy of the treatment, a combinatorial strategy using 17-DMAG as an inhibitor of HSP90 following MHCT was investigated. The effects of combinatorial therapy in terms of cell viability, HSP levels by immunofluorescence and gene expression analysis, oxidative stress generation, and alterations in cellular integrity were evaluated, where combinatorial therapy demonstrated an enhanced therapeutic outcome with maximum glioma cell death. Further, in the murine glioma model, a rapid tumor inhibition of 65 and 53% was observed within 8 days at the primary and secondary tumor sites, respectively, in the MCHT + 17-DMAG group, with abscopal effect-mediated complete tumor inhibition at both the tumor sites within 20 days of MHCT. The extracellularly released HSP90 from dying tumor cells further suggested the induction of immune response supported by the upregulation of IFN-γ and calreticulin genes in the MHCT + 17-DMAG group. Overall, our findings indicate that MHCT activates host immune systems and efficiently cooperates with the HSP90 blockade to inhibit the growth of distant metastatic tumors.

Implementing personalized lung cancer care with spatial profiling, patient derived organoids, and rationally designed drug testing.

e20521 Background: Lung cancer (LC) remains the leading cause of cancer-related death in 2024, with most LC diagnoses with non-small cell lung cancer (NSCLC) subtype. Tyrosine kinase inhibitors (TKI) and targeted therapy against oncogenic drivers (KRAS, EGFR, or ALK fusions, others) are effective initial therapies; however, nearly all treated patients eventually develop resistance to therapy. Key reasons are the focus on limited predictive biomarkers and lack of patient derived LC models that reflect the underlying heterogeneity and the various phenotypic cell states among subclones within and between patients. Methods: We report the establishment of a novel platform for personalized LC care by refining the resolution of molecular interrogation of diagnostic and resistance biopsies to the single cell level, and with spatial profiling using single cell spatial multiomic (scSpMO) and coupling these enhanced diagnostic tools with functional validation with rational designed drug screens in patient-derived organoids (PDOs). Results: For deriving LC PDOs in epithelial and tumor microenvironment (TME) conditions to faithfully maintain the histological and genetic features of their respective LC tissues, we developed enrichment conditions for LC PDOs guided by tumor mutation variants and activated pathways. PDOs are maintained under the same treatment condition in the clinic (e.g., Lorlatinib) and drug testing is tailored to identify potentially most effective next lines of therapy. With nine patients enrolled and others in ongoing studies, single cell PDOs (at > 80% establishment rate) were used to determine activated pathways, lineage plasticity and acquired resistance. Functional assays for acquired resistance such as PI3K/AKT signaling, Src kinase, BRAF fusion and MET hyperactivity allow the identification of potentially novel lines of therapy and treatment sequence and/or combinations for each patient, through the compassionate care program and/or trial participation. Conclusions: Our platform when empowered by combining datasets from scRNA-seq and scSpMO signatures, with validated functional drug responses in PDOs, offers the ability to perform high-content assays, predict and/or act on resistance to therapy for each patient, and provides a path for precision medicine-guided impact on patient care.

Tumor microenvironment activated and amplified self-luminescent nano photosensitizers for efficient treatment of triple negative breast cancer

Triple negative cancer (TNBC) is characterized as an aggressive phenotype lacking a specific therapeutic target. To date, self-illuminating photodynamic therapy (PDT) based on chemiluminescence resonance energy transfer (CRET) has emerged as a potential alternative for TNBC treatment by generating singlet oxygen (1O2), overcoming limitations in light penetration. However, this self-illuminating strategy heavily relies on endogenous hydrogen peroxide (H2O2) and oxygen (O2) within the tumor microenvironment (TME), resulting in inefficient therapeutic performance. In this study, we designed CLT@DPD nanoparticles capable of self-illumination via CRET and TME regulation through self-supplying H2O2 and O2. This nanoparticle was constructed by encapsulating luminol-tetreaphenylporphyrin conjugate (LT) and nanoscale CaO2 with DSPE-PEG 2000 and dioleoylphosphatidylcholine (DOPC). A good accumulation at tumor site was achieved due to enhanced permeability and retention (EPR) effect after intravenous injection of CLT@DP. Responsive to the high H2O2 levels and acidic aqueous conditions of TME, LT can be oxidized to produce 1O2via CRET, and the CaO2 can be decomposed to supply H2O2 and O2. Additionally, the presence of DOPC helps to enhance the permeability of the micelle shell under the oxidation of 1O2, thereby accelerating the release of H2O2 and O2. Our proposed nanoparticles exhibit excellent performance in eradicating in situ tumor cells and inhibiting metastasis by simultaneously enhancing self-luminous PDT and alleviating oxygen depletion in TME.

Nano-assemblies overcome cancer multidrug resistance for effectively synergistic chemo-immuno-oncotherapy

The combination of chemotherapy and immunotherapy is the first line treatment for many cancers. However, resistance to chemotherapy is a common phenomenon, as well as the failure of antigen presentation and T cell infiltration are the fundamental obstacle for effective combined oncotherapy. Many studies have clarified the importance of increased reactive oxygen species (ROS) in reducing multidrug resistance (MDR) by disrupting oxidative balance and activating signaling pathways. Here, to modulate immunosuppressive tumor microenvironment (TME) and overcome the cancerous resistance to chemotherapy for effectively tumor killing, the SIM@NPs-PDA/DOX nano-assemblies, was developed to sequentially delivery doxorubicin (DOX), polydopamine (PDA) and simvastatin (SIM) for tumor chemo-immunotherapy. When the nano-assemblies penetrated into tumor TME, PDA and DOX were released by the hypoxia and low acid condition of TME, which sensitized the tumor cells for reducing the tumor resistance against DOX and effectively induced immunogenic tumor cell death (ICD), respectively. The neo-antigen generated by the ICD effect in situ could be greatly presented by the SIM activated dendritic cells (DCs) for specific T cells production. Simultaneously, the released DOX was also expected to kill tumor-associated macrophages (TAMs) for enhancing the specific T cell infiltration. In B16F10 and MCF-7 tumor cells with acquired drug resistance and relevant tumor models, the designed nano-assemblies showed powerful anti-tumor effects by reducing MDR, killing cancer cells and TAMs, promoting CD8+ T cells activation and infiltration. This study provides a novel nano-assemblies for effective onco-immuno-chemotherapy by overcoming cancer multidrug resistance and immuno-depletion.

Multienzyme-Like Polyoxometalate-Based Single-Atom Enzymes for Cancer-Specific Therapy Through Acid-Triggered Nontoxicity-to-Toxicity Transition.

Single-atom enzymes (SAzymes) exhibit great potential for chemodynamic therapy (CDT); while, general application is still challenged by their instability and unavoidable side effects during delivery. Herein, a manganese-based polyoxometalate single-atom enzyme (Mn-POM SAE) is first introduced into tumor-specific CDT, which exhibits tumor microenvironment (TME)-activated transition of nontoxicity-to-toxicity. Different from traditional POM materials, the aggregates of low-toxic Mn-POM SAE nanospheres are obtained at neutral conditions, facilitating efficient delivery and avoiding toxicity problems in normal tissues. Under acid TME conditions, these nanospheres are degraded into smaller units of toxic Mn(II)-PW11; thus, initiating cancer cell-specific therapy. The released active units of Mn(II)-PW11 exhibit excellent multienzyme-like activities (including peroxidase (POD)-like, oxidase (OXD)-like, catalase (CAT)-like, and glutathione peroxidase (Gpx)-like activities) for the synergistic cancer therapy due to the stabilized high valence Mn species (MnIII/MnIV). As demonstrated by both intracellular evaluations and in vivo experiments, ROS is generated to cause damage to lysosome membranes, further facilitating acidification and impaired autophagy to enhance cancer therapy. This study provides a detailed investigation on the acid-triggered releasing of active units and the electron transfer in multienzyme-mimic-like therapy, further enlarging the application of POMs from catalytical engineering into cancer therapy.

Abstract 2906: Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression

Abstract Background: We aim to assess the effect of S-nitrosylation of COX-2 on tumor attributes in models of early breast cancer. COX-2 is involved in tumor progression in many solid cancers. It is a known oncogene in murine breast cancer models, and targetable by NSAIDs. In women, its clinical correlation to breast cancer progression as well as its efficacy as a therapeutic target have yielded mixed results. These incongruities may be due, in part, to a post-translational modification, as COX-2 undergoes S-nitrosylation on Cys-526. Commercially-available antibodies selectively bind to either the S-nitrosylated (SNO-COX-2) or non-nitrosylated (nCOX-2) forms, and immunohistochemical staining of human tissue reveals that the two forms of COX-2 localize to different cellular sites in normal breast tissue and have opposite associations with breast cancer progression (PMID 33298921). Hypothesis: S-Nitrosylated and non-nitrosylated COX-2 have distinct roles in cancer progression. Approach: MCF10DCIS.com is a human breast cancer cell line chosen due to its ability to form DCIS-like (“stage 0”) lesions in culture and xenografting, which can progress to invasion when induced by signals from the tumor microenvironment (TME). Approach 1: Detect extracellular matrix (ECM) and ligand factors that upregulate SNO-COX-2, independently or in ECM/ligand pairs. We utilized a 2D microenvironment microarray (MEMA) and tested 357 TME conditions. Approach 2: Validate TME conditions in 3D culture. Approach 3: Develop a mutant MCF10DCIS.com line in which COX-2 cannot be S-nitrosylated by inducing a single disabling missense mutation at Cys-526 via CRISPR. Results: The MEMA revealed several conditions in which SNO-COX-2 was upregulated, including fibular collagens and SSP1. In 3D culture, increased SNO-COX-2 was associated with the presence of markers for EMT and an invasive growth phenotype, whereas nCOX-2 was not. Following CRISPR transformation, 59 individual MCF10DCIS.com clones were isolated and the target site of each sequenced. We identified 10 heterozygotic clones with the desired mutation, including a classical heterozygote that also retained the WT allele. Ongoing: Current studies include a second round of CRISPR to produce a homozygous mutant cell line as well as validation of the mutant protein. The resulting cell lines will model the loss of COX-2 S-nitrosylation in breast cancer cells while retaining otherwise-functional COX-2. Citation Format: Reuben J. Hoffmann, AeSoon Bensen, Elise de Wilde, James E. Korkola, Pepper Schedin. Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2906.

Abstract 6496: Assessment of tyrosine kinase inhibitor bypass mechanisms in lung cancer using single cell multiomics, patient derived organoids and rationally designed drug screens

Abstract Lung cancer (LC) is the leading cause of cancer-induced mortality, with 350 patients in the US dying from LC daily, the majority from non-small cell lung cancer (NSCLC). Molecular-targeted therapy such as tyrosine kinase inhibitors (TKI) are effective in first and subsequent lines of therapy against oncogenic drivers (KRAS, EGFR, or ALK fusions, others); however, nearly all treated patients progress eventually and run out of therapeutic options. Key reasons are the lack of predictive biomarkers and LC models that reflect the underlying heterogeneity and different phenotypic cell states among subclones within and between patients. Here, we developed a novel platform for refining the resolution of molecular interrogation to the single cell level, using single cell spatial multiomic (scSpMO), coupled with rational designed drug screens in patient-derived organoids (PDOs) from LC biopsies obtained upon progression. By deriving LC PDOs in epithelial and tumor microenvironment (TME) conditions to faithfully maintain the histological and genetic features of their respective LC tissues, we identified enrichment conditions for LC PDOs guided by tumor mutation variants and activated pathways. PDOs are maintained under the same treatment condition in the clinic (e.g., Lorlatinib) and drug testing is tailored to identify next lines of combined therapy. With six patients enrolled and others in ongoing studies, single cell PDOs (at >80% establishment rate) were used to determine key molecular bypass mechanism for resistance to TKI, including on-target variants, driver bypass, lineage plasticity and acquired resistance. Functional assays for acquired resistance such as PI3K/AKT signaling, Src kinase, BRAF fusion and MET hyperactivity allow the identification of potential novel combined lines of therapy for each patient through the compassionate care program and/or trial participation. Our platform when empowered with datasets of bulk, scRNA-seq and scSpMO signatures of primary human NSCLC, together with PDOs offer the ability to perform analysis of LC phenotypes such as lineage transformation in high-content assays, predict and/or act on resistance to therapy and provides a path for precision medicine-guided immediate impact on patient care. Citation Format: Liqiong Liu, Ann Strange, Schuyler Lee, Bifeng Gao, Daniel Merrick, Tejas Patil, James DeGregori, D Ross Camidge, Sharon R. Pine, Hatim E. Sabaawy. Assessment of tyrosine kinase inhibitor bypass mechanisms in lung cancer using single cell multiomics, patient derived organoids and rationally designed drug screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6496.

Abstract 4240: A comprehensive in vitro tumor model: One-stop simultaneous isolation and culture of tumoroids, CAFs and TILs for advancing immuno-oncology research

Abstract The tumor microenvironment (TME), composed of a diverse array of cells, jointly participates in tumor formation and has attracted attention as a direct or indirect therapeutic target. Among the tumor-forming cells, cancer cells, cancer-associated fibroblast (CAF), and tumor-infiltrating lymphocytes (TILs) comprise major proportion and players in tumor biology. Therefore, an in vitro tumor model composed of at least above three major cellular players better mimics a patient’s tumor. Here, we developed a patient-derived tumor model containing tumoroids, CAFs and TILs isolated from the patient’s tumor tissue by using one-stop isolation culture system. Our one-stop culture system utilizes a Transwell-based method that concurrently segregates cancer cells, CAFs, and TILs based on distinct characteristics such as cell size, migration speed, and growth. Lung tumoroids, fibroblasts, and TILs segregated in Matrigel-coated upper Transwell chamber, Transwell pores and in the lower chamber, respectively. Lung tumoroids maintain the patient’s lung cancer tissue characteristics and genetic features during extended in vitro cultivation. Fibroblasts extracted from the Transwell pores exhibit significant similarity to CAFs found in patient tissue. TILs in the lower part of the Transwell chamber closely resemble those found in the original cancer tissue analyzed by FACS. We have also refined the functionality of TILs through a two-week expansion process. Patients’ tumor composed of 0.15 to 95.3 % of EpCAM positive tumor cells, 0.14 to 19.4 % of CD90 positive fibroblasts and 3.98 to 91.2 % of immune cells in FACS analysis. By reassembling three main cellular components of the tumor in a proper proportion, we developed a co-culture platform for a patient-derived tumor model reproducing patient-specific TME conditions. The co-culture platform showed a potential not only for an experimental model but also to use a predictive test of personalized immunotherapy responses for lung cancer patients. Citation Format: YOO RI KO, Sung Min Kim, Hye Seon Park, Se Jin Jang. A comprehensive in vitro tumor model: One-stop simultaneous isolation and culture of tumoroids, CAFs and TILs for advancing immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4240.

Nanoparticle-Catalyzed Transamination under Tumor Microenvironment Conditions: A Novel Tool to Disrupt the Pool of Amino Acids and GSSG in Cancer Cells.

Catalytic cancer therapy targets cancer cells by exploiting the specific characteristics of the tumor microenvironment (TME). TME-based catalytic strategies rely on the use of molecules already present in the TME. Amino groups seem to be a suitable target, given the abundance of proteins and peptides in biological environments. Here we show that catalytic CuFe2O4 nanoparticles are able to foster transaminations with different amino acids and pyruvate, another key molecule present in the TME. We observed a significant in cellulo decrease in glutamine and alanine levels up to 48 h after treatment. In addition, we found that di- and tripeptides also undergo catalytic transamination, thereby extending the range of the effects to other molecules such as glutathione disulfide (GSSG). Mechanistic calculations for GSSG transamination revealed the formation of an imine between the oxo group of pyruvate and the free -NH2 group of GSSG. Our results highlight transamination as alternative to the existing toolbox of catalytic therapies.

Sequential dual-locking strategy using photoactivated Pt(IV)-based metallo-nano prodrug for enhanced chemotherapy and photodynamic efficacy by triggering ferroptosis and macrophage polarization

Selective activation of Pt(IV) prodrugs within tumors has emerged as a promising strategy in tumor treatment. Although progress has been made with photo- and ultrasound-activated Pt(IV) prodrugs, concerns remain over the non-specific activation of photosensitizers (PS) and the potential for phototoxicity and chemical toxicity. In this study, a sequential dual-locked Pt(IV) nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed. The Pt(IV) prodrug was prepared by conjugating PS-locked Pt(IV) to a polymeric core, which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug. Under acidic tumor microenvironment conditions, the metallo-nano prodrug undergoes dissociation of iron, triggering a reduction process in oxaliplatin under light irradiation, resulting in the activation of both chemotherapy and photodynamic therapy (PDT). Additionally, the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages (TAM), thereby enhancing tumor inhibition. The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs, making it a promising new direction in cancer treatment.

Glioblastoma Therapy: Past, Present and Future.

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

Synthesis of cationic gel-coated hydroxyapatite composites for pH- and thermo-responsive drug delivery in tumor microenvironments

Nanomedicine has gained a significant attention in biomedical science and engineering. It involves design and applications of engineered composites for targeted delivery, diagnostics, imaging, and therapeutic efficacy assessment. Herein, multi-stimuli responsive doxorubicin (DOX) loaded composites were prepared and used for controlled anticancer drug release for antitumor efficacy. In this study, we synthesized the HAp@PP composites by coating Pluronic® P123 and branched polyethylenimine (PP nanogel) on hydroxyapatite (HAp) particles. In-vitro cytotoxicity tests emphasized that HAp@PP composites presented a cell viability of more than 80 % before DOX loading. The fabricated HAp@PP–DOX composites indicated a pH-/thermo-reliant DOX release under tumor microenvironment conditions. Furthermore, the Korsmeyer-Peppas kinetic model yielded the best fit for the release of DOX under the conditions studied. The in-vitro assessment revealed that HAp@PP–DOX had a higher effect that free DOX, with a cell viability less than 25 % and 15 %, respectively, at a DOX concentration of 50 μg/mL. In the context of cancer treatment, the composites have the potential to be more effective than traditional chemotherapy by delivering drugs efficiently.

Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer

Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.

Hypoxic Effects on Matrix Metalloproteinases’ Expression in the Tumor Microenvironment and Therapeutic Perspectives

The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases’ (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs’ transcription. The present review focuses on MMPs’ expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.

Noninvasive Radiation Markers Based on Lung Cancer CT Images and Dosimetry Features to Predict the Immune Response to Radiotherapy in Tumor Microenvironment

For lung cancer patients with complex conditions, doctors need to determine treatment plan in combination with changes of immune response during radiotherapy. It was urgent to find a strategy to predict immune response to intervene the treatment at an early stage. The radiotherapy process and tumor microenvironment status of 105 lung cancer patients were tracked and recorded in our hospital from 2019 to 2022, public database TCGA-LUAD/LUSC queue of TCIA image data was downloaded as external verification set. Data was analyzed according to the following methods: First, the 3D slicer software was used to process the CT imageomics data, and the doseomics information was calculated by DVHmetrics package from R software. Then Python was brought in to develop a non-invasive radiation scoring system through machine learning methods (T-test, LASSO, random forest and Xgboost). Finally, combined with the clinical information related to the patient's immune response, a nomogram was made to study the correlation between the score markers and the ratio of CD4 cells/CD8 cells in the tumor microenvironment, the prognosis of lung cancer, as well as the incidence of radiation pneumonia. The radiation markers score formula was obtained with CT imageomics and DVH dosimics features, which achieved an AUC of 0.67-0.75 in predicting CD4/CD8 condition in tumor microenvironment after radiotherapy. It was worth noticing that in predicting the prognosis of lung cancer, it was difficult to distinguish between the radiation score and the patient's survival status (P>0.05). However, we found that the radiation pneumonitis of lung cancer patients in the low score group (42.6%) was significantly higher than that in the high score group (13.4%). Radiation markers score was a non-invasive method to evaluate the immune response of patients with lung cancer, which can be used to predict the incidence of radiation pneumonitis.

A pH-responsive polymer-coated CaO2 as oxygen-generating nanoparticle in situ for enhanced chemo-photodynamic synergistic therapy against tumors

Photodynamic therapy (PDT) has emerged as an efficient strategy for tumor treatment. However, Insufficient amounts of inherent hypoxia and intrinsic hydrogen peroxide (H2O2) in the tumor microenvironment severely constrained PDT, as oxygen is the critical substrate for photosensitivity reaction. Here, a pH-responsive H2O2 and O2 self-supplying hybrid nanoparticle was designed. Through, the calcium peroxide (CaO2) as carriers loading a chemotherapeutic drug a photosensitizer 5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) and doxorubicin (DOX), was covered with polyacrylic acid (PAA) to build up a feature material DOX-TAPP-CaO2@OA@PAA (denoted as DTCOP) through the reverse microemulsion method. In the acidic tumor microenvironment conditions exposing the water-sensitive CaO2 nanocore to generate hydrogen peroxide (H2O2) and O2, the self-supplied O2 alleviates hypoxia to enhance the PDT, and releasing DOX and TAPP. Synthetic characterization shows that the succeeded synthesized Nanocarriers could effectively carry DOX and TAPP to the tumor site and release O2 at the low pH of TME. And the experimental results demonstrated that this interpose exogenous oxygen strategy is efficient at inhibition of tumor growth both in vitro and in vivo. The nanocomposite exhibits excellent biocompatibility and the ability to inhibit tumor growth and has significant potential for the treatment of hypoxic tumors.

Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses.

Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance.