Modulation Of Tumor Microenvironment Research Articles

Immunonutrition modulates tumor microenvironment and optimizes clinical outcomes in gastrointestinal cancer -a pilot study

Immunonutrition modulates tumor microenvironment and optimizes clinical outcomes in gastrointestinal cancer -a pilot study

ICAT-Mediated Crosstalk Between Cervical Cancer Cells and Macrophages Promotes M2-Like Macrophage Polarization to Reinforce Tumor Malignant Behaviors.

Inhibitor of β-catenin and T-cell factor (ICAT) is a classical inhibitor of the Wnt signaling pathway. Nonetheless, our previous work found that ICAT is overexpressed in cervical cancer (CC), resulting in the augmentation of migration and invasion capabilities of CC cells. It remains unclear what molecular mechanism underlies this phenomenon. The interaction between cancer cells and the tumor microenvironment (TME) promotes the outgrowth and metastasis of tumors. Tumor-associated macrophages (TAMs) are a major constituent of the TME and have a significant impact on the advancement of CC. Consequently, our inquiry pertains to the potential of ICAT to facilitate tumor development through its modulation of the cervical TME. In this study, we first verified that ICAT regulated the secretion of cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in CC cells, leading to M2-like macrophage polarization and enhancement of the migration and invasion of CC cells. Furthermore, the system of co-culturing human umbilical vein endothelial cells (HUVECs) with macrophages revealed that depending on the CC cells' overexpression or inhibition of ICAT, the vascular tube formation by HUVECs can be either increased or decreased. Overall, our study indicates that ICAT stimulates M2-like polarization of TAMs via upregulating IL-10 and TGF-β, which results in increased neovascularization, tumor metastasis, and immunosuppression in CC. In upcoming times, inhibiting crosstalk between CC cells and TAMs may be a possible strategy for CC therapy.

Abstract A048: Paricalcitol improves survival in tumor-permissive cancer-associated fibroblast subtype of pancreatic cancers

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with poor survival and limited therapy options. While traditional cytotoxic agents target cancer cells, there has been growing interest in tumor microenvironment (TME) modulation given that desmoplastic stroma and immune suppression are hallmarks of PDAC. Recently, vitamin D agonism has been identified as a potential treatment to normalize the PDAC TME. We have previously described tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of PDAC that independently predict survival, but whether these subtypes are associated with outcomes after TME modulation has not been studied. METHODS: We evaluated the association of treatment outcomes in a Phase 2 trial of neoadjuvant nab-paclitaxel (A), gemcitabine (G), cisplatin (C), and paricalcitol (P) (NCT03138720) and a Phase 2 trial of A+G+C+hydroxychloroquine (HCQ) (NCT04669197) in patients with non-metastatic PDAC. RNA-sequencing was performed on 28 pretreatment biopsy samples. PurIST and DeCAF were used to determine tumor-intrinsic and CAF subtypes, respectively. Clinical variables such as CA19-9 levels, resectability, and overall survival (OS) were examined. RESULTS: For tumor-intrinsic subtypes, 5 tumors (18%) were basal-like and 23 (82%) were classical. For CAF subtypes, 11 (39%) were tumor-permissive (perm)CAF and 17 (61%) were tumor-restraining (rest)CAF. Neither tumor-intrinsic or CAF subtypes were associated with CA19-9 normalization or resectability at time of diagnosis in either trial. OS was available for NCT03138720; patients with basal-like tumors receiving A+G+C+P had worse median survival of 12.3 months compared to 20.9 months for those with classical tumors, although this difference did not reach statistical significance (log-rank P = 0.065). In two independent cohorts of 925 and 129 patients, those with permCAF tumors had an increased hazard ratio of at least 1.5 (P < 0.001) compared to patients with restCAF tumors for OS. Compared to this historical data, we did not find a difference in OS between patients with permCAF tumors (19.5 months) compared to restCAF tumors (19.7 months, log-rank P = 0.56). CONCLUSION: In the study of A+G+C+P, there was a disparity in OS between patients with basal-like vs. classical tumors, in contrast to the interim results of the COMPASS and PASS-01 trials, where patients with basal-like tumors receiving A+G had similar OS compared to patients with classical tumors. Compared to prior analysis, there was no difference in OS for patients with permCAF tumors vs. those with restCAF tumors, which may suggest that either paricalcitol (or the cytotoxic combination) may be of benefit for patients with permCAF tumors and normalize the CAF landscape. Single-agent studies with paired pre- and post-treatment samples are needed to better understand how to best tailor therapy regiments for patients based on tumor subtypes. Citation Format: Jaewon J Lee, Priscilla S Chan, Changfei Luan, Elena V Kharitonova, Naim U Rashid, Xianlu L Peng, Erkut H Borazanci, Jen Jen Yeh. Paricalcitol improves survival in tumor-permissive cancer-associated fibroblast subtype of pancreatic cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A048.

Abstract B041: Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer distinguished by a dense stromal microenvironment. The current investigation delves into the fibroblast-specific STAT3 signaling in the PDAC tumor microenvironment (TME) and its effects on immune cell infiltration and extracellular matrix (ECM) modulation. An association was identified between heightened levels of phosphorylated STAT3 (pSTAT3) in tumor-associated fibroblasts (CAFs) and a more unfavorable prognosis, particularly among male patients. Comparative analysis of gene expression patterns in normal fibroblasts and those deficient in STAT3, extracted from mouse models of pancreatic cancer, unveiled distinct gene expression profiles related to the inflammatory signaling pathway (IL6, ADM, CXCL11, CD80, VEGFA, TGFB1, STC1, STC2). Utilizing ChIP-Seq analysis with an anti-pSTAT3 antibody, it was confirmed that STAT3 binds to the regulatory regions of these genes, supporting its regulatory role in the inflammatory signaling pathway. Moreover, the absence of STAT3 in CAFs resulted in a decline in M2 macrophages and an upsurge in M1 macrophages within the TME, indicating a potential function of STAT3 in influencing macrophage polarization. Noteworthy observations also revealed that STAT3 signaling in CAFs impacts ECM remodeling, as illustrated by reduced collagen deposition. Furthermore, the deficiency of STAT3 in CAFs led to a notable reduction in the quantity of neutrophils within the TME in our mouse model. Additionally, a plausible involvement of STAT3 in neutrophil recruitment and activation through the CXCL1/CXCR2 axis was indicated. Alterations in the infiltration of neutrophils and macrophages due to the absence of STAT3 could profoundly influence the immune response against PDAC. The modified composition of ECM following STAT3 deletion might also impact the infiltration and functioning of immune cells. These outcomes underscore the significance of STAT3 signaling in CAFs as a promising therapeutic target in PDAC, offering potential for modulating the tumor microenvironment, augmenting anti-tumor immunity, and advancing patient outcomes. Citation Format: Samaneh Saberi, Cameron Bumbleburg, Caroline Everett, Julia E Lefler, Victoria Jordan, Lu Han, Sudarshana Sharma, Michael C. Ostrowski. Fibroblast STAT3 Signaling in Pancreatic Cancer: Implications for Immunotherapy and Tumor Microenvironment Modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B041.

Harnessing Gene Editing Technology for Tumor Microenvironment Modulation: An Emerging Anticancer Strategy.

Cancer is a multifaceted disease influenced by both intrinsic cellular traits and extrinsic factors, with the tumor microenvironment (TME) being crucial in its progression. To satisfy their high proliferation and aggressiveness, cancer cell always plunders large amounts of nutrition and releases various signals to the surrounding, forming a dynamic TME with special metabolic, immune, microbial and physical characteristics. Due to the neglect of interactions between tumor cell and TME, traditional cancer therapies often struggle with challenges such as drug resistance, low efficacy, and recurrence. Importantly, with the development of gene editing technologies, particularly the CRISPR-Cas system, offers promising new strategies for cancer treatment. Combined with nanomaterials strategies, CRISPR-Cas technology exhibits precision, affordability, and user-friendliness with reduced side effects, which holds great promise for profoundly altering the TME at a genetic level, potentially leading to lasting anticancer outcomes. This review will delve into how CRISPR-Cas can be leveraged to manipulate the TME, examining its potential as a transformative anticancer therapy.

A nanotheranostics with hypoxia-switchable fluorescence and photothermal effect for hypoxia imaging-guided immunosuppressive tumor microenvironment modulation

Modulating the immunosuppressive tumor immune microenvironment (TIME) is considered a promising strategy for cancer treatment. However, effectively modulating the immunosuppressive TIME within hypoxic zones remains a significant challenge. In this work, we developed a hypoxia-responsive amphiphilic drug carrier using boron-dipyrromethene (BODIPY) dye-modified chitosan (CsB), and then fabricated a hypoxia-targeted nanotheranostic system, named CsBPNs, through self-assembly of CsB and pexidartinib (5-((5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl), PLX3397), an immunotherapeutic drug targeting tumor-associated macrophages (TAMs), for synergistic photothermal/immunotherapy and hypoxia imaging. CsBPNs demonstrated uniform size, good stability, and hypoxia-switchable fluorescence and photothermal effects, enabling deep penetration and hypoxia imaging capacities in three-dimensional tumor cell spheres and tumor tissues. In vitro and in vivo experiments showed that CsBPNs under laser irradiation promoted TAMs repolarization, reversed the immunosuppressive TIME, and enhanced the therapeutic outcome of PLX3397 in solid tumors by facilitating deep delivery into hypoxic regions and synergistic photothermal therapy. This work provides a new strategy for detecting and modulating the immunosuppressive TIME in hypoxic zones, potentially enabling more precise and effective photo-immunotherapy in the future.

Exploring a Novel Role of Glycerol Kinase 1 in Prostate Cancer PC-3 Cells.

Clinically, prostate cancer is infamous for its histological and molecular heterogeneity, which causes great challenges to pinpoint therapy and pharmaceutical development. To overcome these difficulties, researchers are focusing on modulating tumor microenvironment and immune responses in addition to genetic alteration and epigenetic regulation. Here, we aimed to identify potential biomarkers or modulators of prostate cancer by investigating genes specifically altered in prostate cancer cells treated with established anti-cancer agents. Glycerol kinase 1 (GK1) is phosphotransferase encoded on the X chromosome, is associated with the synthesis of triglycerides and glycerophospholipids, and has been mainly studied for X-linked metabolic disorder GK deficiency (GKD). Interestingly, our DNA microarray analysis showed that several anti-cancer agents highly induced the expression of GK1, especially GK1a and GK1b isoforms, in human prostate cancer PC-3 cells. To elucidate the relationship between GK1 and cancer cell death, a human GK1b-specific expression vector was constructed and transfected into the PC-3 cells. Surprisingly, GK1b overexpression dramatically reduced cell viability and significantly accelerated apoptotic cell death. These findings suggest that GK1b may serve as a promising modulator and biomarker of cell death in prostate cancer, offering potential avenues for therapeutic intervention.

A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA).

43 Background: The role of IRAK1 pathway in inflammatory and immune response is established in autoimmune diseases but less well-understood in cancer. Chromosome 1q21.3 CNA detected in plasma cell-free DNA was observed in pts with advanced solid tumors, and associated with IRAK1 upregulation. In preclinical animal models, IRAK1 upregulation promoted tumorigenesis, while its inhibition led to decreased tumor growth. Pacritinib is a JAK2/FLT3 inhibitor that is FDA approved for treatment in myelofibrosis, but also have known activity against IRAK1. We hypothesize that pacritinib may be effective in disease control of pts with plasma 1q21.3 CNA. Methods: A phase Ib/II clinical trial was designed to investigate the efficacy of pacritinib in pts with treatment (rx) refractory solid tumors harboring 1q21.3 CNA. Serial pt tumor and blood samples were collected and analyzed to elucidate the effect of IRAK1 inhibition on tumor microenvironment and systemic immune modulation. Results: 330 patients were screened, 1q21.3 CNA was detected in 30.1% of pts. Highest incidence of 1q21.3 CNA positivity was detected in breast cancer (39.8%), colorectal cancer (39.7%) and lung cancer (36.1%). 12 pts were commenced on rx over 3 dose levels (DL) (DL1: n=6, DL2: n=3, DL3: n=3). At DL1 (200mg BID), no DLTs were observed, but 2 pts had G3 transaminitis attributed to drug/disease, and 1 pt had intolerable G2 rash; decision was made for dose reduction. At DL2 (200mg OM, 100mg ON), no DLTs were observed. Reescalation to 200mg BID (DL3) was carried out with no DLT observed. Pacritinib at 200mg BD was declared the recommended phase II dose in pts with solid tumors. In the dose expansion cohort, 8 pts (4 colorectal cancer, 3 hepatobiliary [HPB] cancer, 1 lung cancer) have been enrolled thus far. No objective responses were observed. Within pts with HPB tumors, 1 pt with pancreatic cancer had a progression-free survival (PFS) of 25.0 weeks, and 1 pt with cholangiocarcinoma had a PFS of 15.9 weeks. Preliminary analysis of serial tumor biopsy samples suggest an expansion of CD8+ T cell population with pacritinib rx. Serial peripheral blood mononuclear cells analysis showed no significant trend in change in CD8+ T cell population, but a predominance of PD-1+ T cells with rx, and also an increase in CD4+ T cell population. In the myeloid cell population, there appears to be decrease in dendritic cell population, but no significant change in trend of macrophage was observed. Conclusions: Pacritinib at 200mg BID is safe and tolerable in pts with solid tumors. IRAK1 inhibition appears to modulate immune cell populations both in the tumor microenvironment and systemic circulation. Dose expansion is underway, with potential signal of disease control in HPB tumors. Clinical trial information: NCT04520269 .

Effect of iPSC-derived NK cells with site-specific integration of CAR19 and IL24 at the rDNA locus on anti-tumor activity and proliferation.

175 Background: The generation of CAR-NK cells using induced pluripotent stem cells (iPSCs) has emerged as a paradigm for manufacturing off-the-shelf cell products for universal immunotherapy. However, enhancing the potency, safety and multi-actions of CAR-NK cells is still full of challenges. Methods: Interleukin 24 (IL24) and CD19-specific chimeric antigen receptor (CAR19) were site-specifically integrated at the ribosomal DNA (rDNA) locus in human iPSCs by using TALENickases. The engineered iPSCs were differentiated into NK (CAR-iNK) cells by adopting a 38-day differentiation protocol followed by expansion using magnetic beads in vitro. Results: Compared with the CAR-iNK cells, IL24 armored CAR-iNK (CAR19-IL24-iNK) cells showed higher cytotoxic capacity and amplification ability in vitro. Meanwhile, CAR19-IL24-iNK cells inhibited tumor progression more effectively and exhibited better survival without significant side effects in the B-ALL (Nalm-6(Luc1))-bearing mouse model. Interestingly, RNA-sequencing analysis suggested that IL24 may enhance iNK cell function by attracting neutrophils and upregulating FAS and TNFSF10-related genes while exerting a direct effect on tumor cells. Conclusions: This study encourages the exploration of IL24 and other molecules to enhance antitumor properties of CAR-NK cells, suggesting a novel strategy to modulate tumor microenvironment while attacking tumor cells with the potential of promising off-the-shelf immunotherapy.

Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

Multifaceted role of FAM210B in hepatocellular carcinoma: Implications for tumour progression, microenvironment modulation and therapeutic selection.

Hepatocellular carcinoma (HCC) is a common and lethal liver cancer characterized by complex aetiology and limited treatment options. FAM210B, implicated in various cancers, is noteworthy for its potential role in the progression and treatment response of HCC. Yet, its expression patterns, functional impacts and correlations with patient outcomes and resistance to therapy are not well understood. We employed a comprehensive methodology to explore the role of FAM210B in HCC, analysing its expression across cancers, subcellular localization and impacts on cell proliferation, invasion, migration, biological enrichment and the immune microenvironment. Additionally, we investigated its expression in single cells, drug sensitivity and relationships with genomic instability, immunotherapy efficacy and key immune checkpoints. While FAM210B expression varied across cancers, there was no notable difference between HCC and normal tissues. Elevated levels of FAM210B were associated with improved survival outcomes. Subcellular analysis located FAM210B in the plasma membrane and cytosol. FAM210B was generally downregulated in HCC, and its suppression significantly enhanced cell proliferation, invasion and migration. Biological enrichment analysis linked FAM210B to metabolic and immune response pathways. Moreover, its expression modified the immune microenvironment of HCC, affecting drug responsiveness and immunotherapy outcomes. High expression levels of FAM202B correlated with increased resistance to sunitinib and enhanced responsiveness to immunotherapy, as evidenced by associations with tumour mutation burden, PDCD1, CTLA4 and TIDE scores. FAM210B exerts a complex influence on HCC, affecting tumour cell behaviour, metabolic pathways, the immune microenvironment and responses to therapy.

Gold Nanodots-Anchored Cobalt Ferrite Nanoflowers as Versatile Tumor Microenvironment Modulators for Reinforced Redox Dyshomeostasis.

Given that tumor microenvironment (TME) exerts adverse impact on the therapeutic response and clinical outcome, robust TME modulators may significantly improve the curative effect and increase survival benefits of cancer patients. Here, Au nanodots-anchored CoFe2O4 nanoflowers with PEGylation (CFAP) are developed to respond to TME cues, aiming to exacerbate redox dyshomeostasis for efficacious antineoplastic therapy under ultrasound (US) irradiation. After uptake by tumor cells, CFAP with glucose oxidase (GOx)-like activity can facilitate glucose depletion and promote the production of H2O2. Multivalent elements of Co(II)/Co(III) and Fe(II)/Fe(III) in CFAP display strong Fenton-like activity for·OH production from H2O2. On the other hand, energy band structure CFAP is superior for US-actuated 1O2 generation, relying on the enhanced separation and retarded recombination of e-/h+ pairs. In addition, catalase-mimic CFAP can react with cytosolic H2O2 to generate molecular oxygen, which may increase the product yields from O2-consuming reactions, such as glucose oxidation and sonosensitization processes. Besides the massive production of reactive oxygen species, CFAP is also capable of exhausting glutathione to devastate intracellular redox balance. Severe immunogenic cell death and effective inhibition of solid tumor by CFAP demonstrates the clinical potency of such heterogeneous structure and may inspire more relevant designs for disease therapy.

Antibody-Drug Conjugates to Promote Immune Surveillance: Lessons Learned from Breast Cancer.

Antibody-drug conjugates (ADCs) represent an effective class of agents for the treatment of several tumor types, including breast cancer (BC), featuring approved molecules such as trastuzumab-emtansine, trastuzumab-deruxtecan, and sacituzumab-govitecan. Immune-checkpoint inhibitors (ICIs) also showed activity in selected BC subtypes, and two agents, pembrolizumab and atezolizumab, are currently approved for the treatment of triple-negative BC patients. The potential synergy between ADCs and immunotherapy in BC remains an area of active investigation. Preclinical studies suggest that ADCs promote immune surveillance, modulating tumor microenvironment, inducing immunogenic cell death, and enhancing antitumor immunity. Translational evidence has shown potential predictive biomarkers for ADCs alone or in combination with immunotherapy, including expression of target antigen, oncogenic pathways, tumor-infiltrating lymphocytes, and neutrophil-to-lymphocyte ratio. Given this background, several clinical trials evaluated ADC-ICI combinations in BC patients, demonstrating promising outcomes with an overall manageable toxicity profile, and many studies are currently ongoing to confirm the efficacy and feasibility of this therapeutic approach. In the present review, we summarized the available evidence about the integration of ADCs and immunotherapy for the management of BC, emphasizing the need for further translational and clinical investigations to optimize this treatment strategy and elucidate predictive biomarkers, eventually improving patient outcomes.

The unfolded protein response machinery in glioblastoma genesis, chemoresistance and as a druggable target.

The role of the unfolded protein response (UPR) has been progressively unveiled over the last decade and several studies have investigated its implication in glioblastoma (GB) development. The UPR restores cellular homeostasis by triggering the folding and clearance of accumulated misfolded proteins in the ER consecutive to endoplasmic reticulum stress. In case it is overwhelmed, it induces apoptotic cell death. Thus, holding a critical role in cell fate decisions. This article, reviews how the UPR is implicated in cell homeostasis maintenance, then surveils the evidence supporting the UPR involvement in GB genesis, progression, angiogenesis, GB stem cell biology, tumor microenvironment modulation, extracellular matrix remodeling, cell fate decision, invasiveness, and grading. Next, it concurs the evidence showing how the UPR mediates GB chemoresistance-related mechanisms. The UPR stress sensors IRE1, PERK, and ATF6 with their regulator GRP78 are upregulated in GB compared to lower grade gliomas and normal brain tissue. They are activated in response to oncogenes and are implicated at different stages of GB progression, from its genesis to chemoresistance and relapse. The UPR arms can be effectors of apoptosis as mediators or targets. Recent research has established the role of the UPR in GB pathophysiology and chemoresistance. Targeting its different sensors have shown promising in overcoming GB chomo- and radioresistance and inducing apoptosis.

Boron Dipyrromethene-Based Nanotheranostic System for Sonophotoassisted Therapy and Simultaneous Monitoring of Tumor Immune Microenvironment Reprogramming.

Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-β (TGF-β) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.

Breast Cancer Treatment Strategies Targeting the Tumor Microenvironment: How to Convert "Cold" Tumors to "Hot" Tumors.

Breast cancer characterized as "cold tumors" exhibit low levels of immune cell infiltration, which limits the efficacy of conventional immunotherapy. Recent studies have focused on strategies using nanotechnology combined with tumor microenvironment modulation to transform "cold tumors" into "hot tumors". This approach involves the use of functionalized nanoparticles that target and modify the tumor microenvironment to promote the infiltration and activation of antitumor immune cells. By delivering immune activators or blocking immunosuppressive signals, these nanoparticles activate otherwise dormant immune responses, enhancing tumor immunogenicity and the therapeutic response. These strategies not only promise to increase the response rate of breast cancer patients to existing immunotherapies but also may pave new therapeutic avenues, providing a new direction for the immunotherapy of breast cancer.

CD40 agonist engineered immunosomes modulated tumor microenvironment and showed pro-immunogenic response, reduced toxicity, and tumor free survival in mice bearing glioblastoma

CD40 agonist antibodies (αCD40) have shown promising anti-tumor response in both preclinical and early clinical studies. However, its systemic administration is associated with immune- and hepato-toxicities which hampers its clinical usage. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it. Immunosomes showed higher tumor accumulation till 96 h of administration and displayed sustained release of αCD40 in vivo. Immunosomes significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+ cells in TME. Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the PD-L1 expression. Moreover, Immunosomes significantly enhanced the levels of Th1 cytokines (IFN-γ, IL-6, IL-2) over Th2 cytokines (IL-4 and IL-10) which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.

Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC. In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo. Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses. RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

Concerting magnesium implant degradation facilitates local chemotherapy in tumor-associated bone defect

Effective management of malignant tumor-induced bone defects remains challenging due to severe systemic side effects, substantial tumor recurrence, and long-lasting bone reconstruction post tumor resection. Magnesium and its alloys have recently emerged in clinics as orthopedics implantable metals but mostly restricted to mechanical devices. Here, by deposition of calcium-based bilayer coating on the surface, a Mg-based composite implant platform is developed with tailored degradation characteristics, simultaneously integrated with chemotherapeutic (Taxol) loading capacity. The delicate modulation of Mg degradation occurring in aqueous environment is observed to play dual roles, not only in eliciting desirable osteoinductivity, but allows for modification of tumor microenvironment (TME) owing to the continuous release of degradation products. Specifically, the sustainable H2 evolution and Ca2+ from the implant is distinguished to cooperate with local Taxol delivery to achieve superior antineoplastic activity through activating Cyt-c pathway to induce mitochondrial dysfunction, which in turn leads to significant tumor-growth inhibition in vivo. In addition, the local chemotherapeutic delivery of the implant minimizes toxicity and side effects, but markedly fosters osteogenesis and bone repair with appropriate structure degradation in rat femoral defect model. Taken together, a promising intraosseous administration strategy with biodegradable Mg-based implants to facilitate tumor-associated bone defect is proposed.