Reprogramming Of Tumor Microenvironment Research Articles

HIF1α epigenetically repressed macrophages via CRISPR/Cas9-EZH2 system for enhanced cancer immunotherapy

Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy. In this study, we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment. Epigenetically silencing of Hif1α via histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system, in which histone H3 methylase EZH2 was recruited to the promoter region specifically. The Hif1α silenced macrophage, namely HERM (Hif1α Epigenetically Repressed Macrophage) manifested as inheritable tumor suppressing phenotype. In the subcutaneous B16-F10 melanoma syngeneic model, intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one, reducing tumor burden and prolonging overall survival. Additionally, HERMs therapy remarkably inhibited tumor angiogenesis. Together, our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment, but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages.

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer.

Most, if not all, aspects of carcinogenesis are influenced by the tumor microenvironment (TME), a complex architecture of cells, matrix components, soluble signals, and their dynamic interactions in the context of physical traits of the tissue. Expanding application of technologies for high-dimensional analyses with single-cell resolution has begun to decipher the contributions of the immune system to cancer progression and its implications for therapy. In this review, we will discuss the multifaceted roles of tumor-associated macrophages and neutrophils, focusing on factors that subvert tissue immune homeostasis and offer therapeutic opportunities for TME reprogramming. By performing a critical analysis of available datasets, we elaborate on diversification mechanisms and unifying principles of myeloid cell heterogeneity in human tumors.

Distinct functions of transforming growth factor-\u03b2 signaling in c-MYC driven hepatocellular carcinoma initiation and progression

Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.

Targeting ferroptosis-based cancer therapy using nanomaterials: strategies and applications.

As an iron-dependent mode of programmed cell death induced by lipid peroxidation, ferroptosis plays an important role in cancer therapy. The metabolic reprogramming in tumor microenvironment allows the possibility of targeting ferroptosis in cancer treatment. Recent studies reveal that nanomaterials targeting ferroptosis have prospects for the development of new cancer treatments. However, the design ideas of nanomaterials targeting ferroptosis sometimes vary. Therefore, in addition to the need for a systematic summary of these ideas, new ideas and insights are needed to make possible the construction of nanomaterials for effectively targeting this cell death pathway. At the same time, further optimization of nanomaterials design is required to make them appropriate for clinical treatment. In this context, we summarize this cross-cutting research area covering from the known mechanism of ferroptosis to providing feasible ideas for nanomaterials design as well as their clinical application. We aim to provide new insights and enlightenment for the next step in developing new nanomaterials for cancer treatment.

Tracer-Based Cancer Metabolomic Analysis.

Metabolic rewiring/reprogramming is an essential hallmark of cancer. Alteration of metabolic phenotypes is occurred in cancer cells in response to a harsh condition to support cancer cell proliferation, survival, and metastasis. Stable isotope can be used as a tracer to investigate the redistribution of the carbons labeled in glucose in order to elucidate the detailed mechanisms of cellular rewiring and reprogramming in tumor microenvironment. Stable isotope-resolved metabolomics (SIRM) is an analytical method inferring metabolic networking by using advanced nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to analyze the fate of a single atom from a stable isotope-enriched precursor to a product metabolite. This methodology has been demonstrated for a wide range of biological applications, including cancer metabolomic analysis. The basic principle and platforms of SIRM and its implication for cancer metabolism research will be addressed in this chapter.

Exosomes: Critical Mediators of Tumour Microenvironment Reprogramming.

Tumour microenvironment (TME) is a resident of a variety of cells, which are devoted to the heterogeneous population of the tumour. TME establishes a communication network for crosstalk and signalling between tumour cells, stroma, and other interstitial cells. The cross-communication drives the reprogramming of TME cells, which promote cancer progression and metastasis via diverse signalling pathways. Recently, TMEderived exosomes are recognized as critical communicators of TME cell reprogramming. This review addresses the role of TME-derived exosomes in the modulation of stroma, including reprogramming the stromal cells, ECM and tumour cell metabolism, as well as neoplastic transformation. Subsequently, we described the role of exosomes in pre-metastatic niche development, maintenance of stemness and tumour vasculature, as well as development of drug resistance. We also explored tumour-derived exosomes in precision, including diagnosis, drug delivery, and vaccine development. We discussed the currently established bioengineered exosomes as carriers for chemotherapeutic drugs, RNAi molecules, and natural compounds. Finally, we presented tetraspanin and DNA-based precision methods for the quantification of tumour-derived exosomes. Overall, TMEderived exosome-mediated reprogramming of TME and precision strategies could illuminate the potential mechanisms for targeted therapeutic intervention.

Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment

Immunotherapy has gained increasing focus in treating pancreatic ductal adenocarcinoma (PDAC), since conventional therapies like chemotherapy could not provide satisfactory improvement in overall survival outcome of PDAC patients. However, it is still not the game changing solution due to the unique tumor microenvironment and low cancer immunogenicity of PDAC. Thus, inducing more intratumoral effector immune cells as well as reversing immunosuppression is the core of PDAC treatment. Herein, we demonstrate an exosome-based dual delivery biosystem for enhancing PDAC immunotherapy as well as reversing tumor immunosuppression of M2-like tumor associated macrophages (M2-TAMs) upon disruption of galectin-9/dectin 1 axis. The deliver system is constructed from bone marrow mesenchymal stem cell (BM-MSC) exosomes, electroporation-loaded galectin-9 siRNA, and surficially modified with oxaliplatin (OXA) prodrug as an immunogenic cell death (ICD)-trigger. The use of biomaterials, BM-MSC exosomes, can significantly improve tumor targeting efficacy, thus increasing drug accumulation in the tumor site. The combined therapy (iEXO-OXA) elicits anti-tumor immunity through tumor-suppressive macrophage polarization, cytotoxic T lymphocytes recruitment and Tregs downregulation, and achieves significant therapeutic efficacy in cancer treatment.

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.

Limited clinical benefit has been demonstrated for chimeric antigen receptor (CAR) therapy of solid tumors, but coengineering strategies to generate so-called fourth-generation (4G) CAR-T cells are advancing toward overcoming barriers in the tumor microenvironment (TME) for improved responses. In large part due to technical challenges, there are relatively few preclinical CAR therapy studies in immunocompetent, syngeneic tumor-bearing mice. Here, we describe optimized methods for the efficient retroviral transduction and expansion of murine T lymphocytes of a predominantly central memory T cell (TCM cell) phenotype. We present a bicistronic retroviral vector encoding both a tumor vasculature-targeted CAR and murine interleukin-15 (mIL-15), conferring enhanced effector functions, engraftment, tumor control, and TME reprogramming, including NK cell activation and reduced presence of M2 macrophages. The 4G-CAR-T cells coexpressing mIL-15 were further characterized by up-regulation of the antiapoptotic marker Bcl-2 and lower cell-surface expression of the inhibitory receptor PD-1. Overall, this work introduces robust tools for the development and evaluation of 4G-CAR-T cells in immunocompetent mice, an important step toward the acceleration of effective therapies reaching the clinic.

Biomineralized Bacterial Outer Membrane Vesicles Potentiate Safe and Efficient Tumor Microenvironment Reprogramming for Anticancer Therapy.

The highly immunosuppressive tumor microenvironment (TME) in solid tumors often dampens the efficacy of immunotherapy. In this study, bacterial outer membrane vesicles (OMVs) are demonstrated as powerful immunostimulants for TME reprogramming. To overcome the obstacles of antibody-dependent clearance and high toxicity induced by OMVs upon intravenous injection (a classic clinically relevant delivery mode), calcium phosphate (CaP) shells are employed to cover the surface of OMVs, which enables potent OMV-based TME reprograming without side effects. Meanwhile, the pH-sensitive CaP shells facilitate the neutralization of acidic TME, leading to highly beneficial M2-to-M1 polarization of macrophages for improved antitumor effect. Moreover, the outer shells can be integrated with functional components like folic acid or photosensitizer agents, which facilitates the use of the OMV-based platform in combination therapies for a synergic therapeutic effect.

Abstract A07: Role of the class IA PI3K p110β subunit in pancreatic cancer

Abstract Introduction: Class I PI3K signaling is constitutively active and correlated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). The modest effect of pan-PI3Ks inhibitors (targeting all p110 isoforms) clinically tested on different types of cancer highlighted the need to understand the roles of each PI3K isoform in cancer cell, with isoform-specific inhibitors of PI3K and murine models that conditionally target their activity. My team has developed unique mouse models that recapitulate the carcinogenesis of PDAC and that conditionally target the activity of p110α or p110β specifically in pancreatic epithelial cells. Methods: We analyzed the biologic impact of pancreas-restricted genetic inactivation of p110β during pancreatic cancer progression induced by oncogenic Kras with or without mutated p53 combined with experimentally induced risk factor conditions such as inflammation. In particular, we searched the mechanisms of action of p110β in pancreatic cancerogenesis and in lesion-driven stroma formation. Results: Inhibition of p110β prevented tumor progression towards metastatic cancer and led to the formation of low-grade neoplastic lesions, demonstrating the role of this isoform in pancreatic carcinogenesis. We found that upon genetic inactivation of the p110β isoform, the only present lesions are duct-like preneoplastic structures. Besides, mice harboring genetic inactivation of p110β in their pancreas are protected from mutated Kras and p53-induced lethality. Interestingly, p110β inactivation in pancreatic epithelial cells is responsible for changing the immune cell recruitment and the stromal response to epithelial oncogenic Kras signal or to inflammation. Conclusion: Our data suggest that p110β in pancreatic lineage plays an important role in murine pancreatic cancer initiation induced by genetic alterations commonly found in pancreatic cancer, by impacting cell dedifferentiation and reprogramming tumor microenvironment. Citation Format: Silvia Arcucci, Nicole Therville, Céline Basset, Aurélie Vertut, Julie Guillermet-Guibert. Role of the class IA PI3K p110β subunit in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A07.

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming.

The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkers and therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia is a condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In this study, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing a new clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expression profiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to four existing data sets. Analyses took advantage of machine learning methods. We identified NB-hop, a seven-gene hypoxia biomarker, as a predictor of NB patient prognosis, which is able to discriminate between two populations of patients with unfavorable or favorable outcome on a molecular basis. NB-hop retained its prognostic value in a multivariate model adjusted for established risk factors and was able to additionally stratify clinically relevant groups of patients. Tumors with an unfavorable NB-hop expression showed a significant association with telomerase activation and a hypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment. NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosis and it represents a critical factor for the stratification and treatment of NB patients.

Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)phenyl-2,4-dinitrobenzenesulfonate and Fe3+ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.

Abstract 5683: Single-cell RNA-seq reveals heterogeneity, clonal evolution and strategies to overcome ibrutinib-venetoclax dual resistance in mantle cell lymphoma

Abstract Introduction The clinical, pathological, genetic, and transcriptomic characteristics of mantle cell lymphoma (MCL) are extremely heterogeneous, and MCL patients frequently develop therapeutic resistance after frontline therapies. In this study, we performed longitudinal transcriptomic analysis on patient specimens at the single-cell level, aiming to understand the dynamic and complex cellular and molecular changes underlying therapeutic resistance and to identify potential targets to overcome dual resistance to ibrutinib and venetoclax. Methods Single-cell RNA-seq was performed on sequential MCL patient specimens. Integrative computational approaches were employed to characterize the cellular and molecular basis of therapeutic resistance and clonal evolution. Bulk RNA sequencing, deep WES, and 17-color flow analysis of multiple patient cohorts were used to validate the novel findings. An orthotopic PDX model derived from one of the ibrutinib-venetoclax non-responders was used for further analysis and to investigate the in vivo efficacy of therapeutic agents against multiple actionable targets. Results To dissect the inter- and intra-tumor heterogeneity underlying the therapeutic resistance, we performed sequential scRNA-seq analysis of 21 specimens (18,794 cells in total) collected from 3 ibrutinib responders and 2 ibrutinib-venetoclax non-responders along the course of ibrutinib and/or venetoclax treatments. The analysis revealed a high degree of inter- and intra-tumor heterogeneity with distinct cellular and transcriptomic profiling within and across ibrutinib-responders and ibrutinib-venetoclax non-responders. The observed transcriptomic evolution of cancer hallmarks associated with disease progression and therapeutic resistance were faithfully passed onto the orthotopic PDX model derived from one of the ibrutinib-venetoclax non-responders. We tracked the clinical ibrutinib-induced lymphocytosis at a single-cell level in ibrutinib responders and disease progression-associated clonal evolution in non-responders, which was validated by deep WES analysis. 17q gain in non-responders was further validated in a larger patient cohort. Our analysis revealed the reprogramming of tumor microenvironment and tumor immune evasion, which was further validated by 17-color flow analysis in a large cohort (n = 70). Inhibition of multiple actionable targets showed effective anti-MCL activity in the PDX model to overcome the ibrutinib-venetoclax dual resistance. Conclusions This study demonstrates the potential of longitudinal single-cell transcriptomic analysis to reveal the molecular mechanisms underlying tumor heterogeneity, clonal evolution, disease progression, and therapeutic resistance, and to identify potential novel targets to circumvent therapeutic resistance in MCL and other diseases. Citation Format: Changying Jiang, Shaojun Zhang, Yuanxin Wang, Rongjia Zhang, Yang Liu, Joseph McIntosh, Guangchun Han, Ruiping Wang, David Santos, Maria Badillo, Angela Leeming, Zhihong Chen, Kimberly Hartig, John Bigcal, Hun Lee, Raphael Steiner, Jorge Romaguera, Preetesh Jain, Krystle Nomie, Andy Futreal, Linghua Wang, Michael Wang. Single-cell RNA-seq reveals heterogeneity, clonal evolution and strategies to overcome ibrutinib-venetoclax dual resistance in mantle cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5683.

Abstract 6057: Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment

Abstract During the transition from healthy tissue to cancer and metastasis, the tumor microenvironment (TME) initiates crucial changes that licenses the progression from primary tumors to aggressive and metastatic disease. Our understanding of the specific factors and molecular mechanisms underpinning these transitions in the TME is critical for influencing the potency and scope of existing cancer therapy strategies but is still evolving and subject to substantial and widespread investigations. Here we uncover a novel molecular mechanism actioned by fibroblasts in the TME to modulate the secretion of the vascular endothelial growth factor (VEFG) via the hypoxia-inducible transcription factor (HIF1α). Utilizing primary human cells co-culture systems in combination with highly potent and selective USP7 inhibitors, we demonstrate that the deubiquitinating enzyme USP7 modulates the stability of HIF1α in primary human fibroblasts and secreted VEGF levels in primary fibroblasts as well as cancer-associated fibroblasts. This USP7-mediated modulation of VEGF secretion in the TME does not occur in cancer cells, immune cells or endothelial cells, rather it is restricted to the fibroblastic compartment. Importantly, the modulation of VEGF secretion by USP7 in fibroblasts is not mediated via the Mdm2 axis: Mdm2 antagonists are unable to recapitulate the VEGF modulation in fibroblasts. Knock-down of USP7 in primary fibroblasts validates the phenotype obtained with potent and selective USP7 inhibitors. In line with their effects on the TME in primary cell cultures, potent, selective USP7 inhibitors demonstrated tumour growth inhibition in vivo in a syngeneic cancer xenograft model that does not respond to USP7 inhibitors in vitro. Collectively, our studies reveal a molecular mechanism whereby USP7 inhibition leads to TME reprogramming mediated by an increased destabilization of HIF1α leading to reduced levels of VEGF in the TME and improved anti-tumor activity. Our results support further investigations of combination of a USP7 inhibitor with immune checkpoint inhibitors, as well as other TME modulating agents. Citation Format: Xavier Jacq, Anamarija Jurisic, Julien Daubriac, Ian T. Lobb, Mark Wappett, Aaron Cranston, Peggy Sung, Gerald Gavory, Colin O'Dowd, Tim Harisson. Discovery of a novel function for USP7 inhibitors: Reprogramming the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6057.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Immunomodulation via macrophages to fight solid tumor malignancies

The paper 'A C-Terminal Fragment of Adhesion Protein Fibulin-7 Inhibits Growth of Murine Breast Tumor by Regulating Macrophage Reprogramming' by Chakraborty et al. highlights that Fbln7-C could be explored as a potential immunomodulatory agent against various solid cancers and have shown its abilities to regulate tumor microenvironment reprogramming of TAMs in a breast cancer model. Fbln7, which is a secreted glycoprotein, has been shown to be anti-angiogenic and has an immunomodulatory role regulating various functional properties of monocytes, macrophages, and neutrophils, thereby influencing inflammation. In this study, the authors have shown that in a murine breast tumor model, intravenous administration of Fbln7-C significantly reduces the size of tumors via macrophage reprogramming. Comment on: https://doi.org/10.1111/febs.15333.

Defining the tumor cell: CA-MSC interactions which mediate ovarian cancer metastasis.

e18072 Background: Carcinoma-associated mesenchymal stem cells (CA-MSCs) are mesenchymal stem cells (MSCs) within the tumor microenvironment (TME). We demonstrated that CA-MSCs promote ovarian cancer chemotherapy resistance through paracrine signaling with ovarian cancer cells, interact with ovarian cancer cells to form mixed-cellularity complexes which enhance metastasis, and arise from cancer cell and TME reprogramming of normal tissue MSCs. To identify mediators of the CA-MSC:tumor cell interaction, we investigated the role of tetraspanins, which are membrane-spanning proteins that have been implicated in cancer development and metastasis by influencing cell adhesion and cell-cell interactions. The tetraspanins CD9, CD81, CD151, and CD63 were identified as potential mediators of cell surface interactions between ovarian cancer cells and CA-MSCs through homo- and heterodimerization. Methods: Td-labeled OVCAR3 cancer cells were co-cultured with 3 patient-derived MSC (derived from normal tissue) and 3 patient-derived CA-MSC (derived from malignant tissue) cell lines. Flow cytometry was performed to measure surface protein expression of the tetraspanins CD9, CD81, CD151, and CD63, and was compared to control cells (not co-cultured) and their median fluorescence intensity (MFI). We next separated OVCAR3 cells co-cultured with MSCs or CA-MSCs using fluorescent activated cell sorting (FACS) based on Td expression. Following FACS, tetraspanin expression in OVCAR3 cells, MSCs, and CA-MSCs was assessed via qRT-PCR and western blotting, and compared to cell lines that were not co-cultured. Results: Flow cytometric analysis revealed an increase in MFI of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs when compared to non-co-cultured matched cells. Increased RNA expression of CD9, CD151, and CD63 was seen in OVCAR3 cells that were co-cultured with CA-MSCs or MSCs when compared to non-co-cultured OVCAR3 cells. Increased RNA expression of CD81 and CD63 was noted in both co-cultured CA-MSCs and MSCs compared to non-co-cultured cells. Lastly, western blotting demonstrated increased protein expression of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs compared to non-co-cultured matched cells. Conclusions: These results indicate that direct interactions between OVCAR3 cells and CA-MSCs or MSCs lead to overexpression of specific tetraspanins at the RNA and protein levels, implying that they may be facilitating tumor cell:CA-MSC and tumor cell:MSC binding.

Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial

BackgroundPrevious trials showed that antiangiogenesis or anti-programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) monotherapy only showed marginal effect in triple-negative breast cancer (TNBC). Preclinical studies demonstrated that antiangiogenic therapy...

Reprogramming Tumor Microenvironment with Photothermal Therapy.

The tumor microenvironment significantly influences cancer progression and therapeutic response. Reprogramming of tumor microenvironment has emerged as a strategy to assist conventional cancer treatment. In recent years, photothermal therapy has received considerable attention owing to its noninvasiveness, high temporal-spatial resolution, and minimal drug resistance. Apart from ablating cancer cells by generating heat upon light irradiation, photothermal therapy can also affect the tumor microenvironment, such as disrupting the tumor extracellular matrix and tumor vasculature. Moreover, cancer cell death by hyperthermia could potentially activate the immune system to fight against tumor. In this topical review, we focus on the recent progress of photothermal therapy based on tumor microenvironment remodeling, aiming to better guide the design of nanoparticles for cancer photoimmunotherapy.

Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer.

Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.