Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Epigenetic alterations fuel brain metastasis via regulating inflammatory cascade.

Brain metastasis (BrM) is a major threat to the survival of melanoma, breast, and lung cancer patients. Circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and sustain in the brain microenvironment. Genetic mutations and epigenetic modifications have been found to be critical in controlling key aspects of cancer metastasis. Metastasizing cells confront inflammation and gradually adapt in the unique brain microenvironment. Currently, it is one of the major areas that has gained momentum. Researchers are interested in the factors that modulate neuroinflammation during BrM. We review here various epigenetic factors and mechanisms modulating neuroinflammation and how this helps CTCs to adapt and survive in the brain microenvironment. Since epigenetic changes could be modulated by targeting enzymes such as histone/DNA methyltransferase, deacetylases, acetyltransferases, and demethylases, we also summarize our current understanding of potential drugs targeting various aspects of epigenetic regulation in BrM.

Racial disparity in prostate cancer: an outlook in genetic and molecular landscape.

Prostate cancer (PCa) incidence, morbidity, and mortality rates are significantly impacted by racial disparities. Despite innovative therapeutic approaches and advancements in prevention, men of African American (AA) ancestry are at a higher risk of developing PCa and have a more aggressive and metastatic form of the disease at the time of initial PCa diagnosis than other races. Research on PCa has underlined the biological and molecular basis of racial disparity and emphasized the genetic aspect as the fundamental component of racial inequality. Furthermore, the lower enrollment rate, limited access to national-level cancer facilities, and deferred treatment of AA men and other minorities are hurdles in improving the outcomes of PCa patients. This review provides the most up-to-date information on various biological and molecular contributing factors, such as the single nucleotide polymorphisms (SNPs), mutational spectrum, altered chromosomal loci, differential gene expression, transcriptome analysis, epigenetic factors, tumor microenvironment (TME), and immune modulation of PCa racial disparities. This review also highlights future research avenues to explore the underlying biological factors contributing to PCa disparities, particularly in men of African ancestry.

Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. METHODS: Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF-conditioned medium and RNA sequencing data of acinar cells post-conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs). RESULTS: A close association of acino-ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation. CONCLUSIONS: Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception.

MicroRNA-1: Diverse role of a small player in multiple cancers.

The process of cancer initiation and development is a dynamic and complex mechanism involving multiple genetic and non-genetic variations. With the development of high throughput techniques like next-generation sequencing, the field of cancer biology extended beyond the protein-coding genes. It brought the functional role of noncoding RNAs into cancer-associated pathways. MicroRNAs (miRNAs) are one such class of noncoding RNAs regulating different cancer development aspects, including progression and metastasis. MicroRNA-1 (miR-1) is a highly conserved miRNA with a functional role in developing skeletal muscle precursor cells and cardiomyocytes and acts as a consistent tumor suppressor gene. In humans, two discrete genes, MIR-1-1 located on 20q13.333 and MIR-1-2 located on 18q11.2 loci encode for a single mature miR-1. Downregulation of miR-1 has been demonstrated in multiple cancers, including lung, breast, liver, prostate, colorectal, pancreatic, medulloblastoma, and gastric cancer. A vast number of studies have shown that miR-1 affects the hallmarks of cancer like proliferation, invasion and metastasis, apoptosis, angiogenesis, chemosensitization, and immune modulation. The potential therapeutic applications of miR-1 in multiple cancer pathways provide a novel platform for developing anticancer therapies. This review focuses on the different antitumorigenic and therapeutic aspects of miR-1, including how it regulates tumor development and associated immunomodulatory functions.

Metabolic Rewiring and Stemness: A Critical Attribute of Pancreatic Cancer Progression.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases with a poor 5-year survival rate. PDAC cells rely on various metabolic pathways to fuel their unlimited proliferation and metastasis. Reprogramming glucose, fatty acid, amino acid, and nucleic acid metabolisms contributes to PDAC cell growth. Cancer stem cells are the primary cell types that play a critical role in the progression and aggressiveness of PDAC. Emerging studies indicate that the cancer stem cells in PDAC tumors are heterogeneous and show specific metabolic dependencies. In addition, understanding specific metabolic signatures and factors that regulate these metabolic alterations in the cancer stem cells of PDAC paves the way for developing novel therapeutic strategies targeting CSCs. In this review, we discuss the current understanding of PDAC metabolism by specifically exploring the metabolic dependencies of cancer stem cells. We also review the current knowledge of targeting these metabolic factors that regulate CSC maintenance and PDAC progression.

GPCRs and fibroblast heterogeneity in fibroblast-associated diseases.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of "most targeted receptors". About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies.

MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy.

Pancreatic cancer (PC) is a highly lethal malignancy with a dismal five-year survival rate. This is due to its asymptomatic nature, lack of reliable biomarkers, poor resectability, early metastasis, and high recurrence rate. Limited efficacies of current treatment modalities treatment-associated toxicity underscore the need for the development of immunotherapy-based approaches. For non-resectable, locally advanced metastatic PC, immunotherapy-based approaches including vaccines, antibody-targeted, immune checkpoint inhibition, CAR-T-cells, and adoptive T-cell transfer could be valuable additions to existing treatment modalities. Thus far, the vaccine candidates in PC have demonstrated modest immunological responses in different treatment modalities. The identification of tumor-associated antigens (TAA) and their successful implication in PC treatment is still a challenge. MUC4, a high molecular weight glycoprotein that functionally contributes to PC pathogenesis, is an attractive TAA. It is not detected in the normal pancreas; however, it is overexpressed in mouse and human pancreatic tumors. The recombinant MUC4 domain, as well as predicted immunogenic T-cell epitopes, elicited cellular and humoral anti-MUC4 response, suggesting its ulility as a vaccine candidate for PC therapy. Existence of PC-associated MUC4 splice variants, autoantibodies against overexpressed and aberrantly glycosylated MUC4 and presence of T-cell clones against the mutations present in MUC4 further reinforce its significance as a tumor antigen for vaccine development. Herein, we review the significance of MUC4 as a tumor antigen in PC immunotherapy and discuss both, the development and challenges associated with MUC4 based immunotherapy. Lastly, we will present our perspective on MUC4 antigenicity for the future development of MUC4-based PC immunotherapy.

Chemokines network in bone metastasis: Vital regulators of seeding and soiling.

Chemokines are well equipped with chemo-attractive signals that can regulate cancer cell trafficking to specific organ sites. Currently, updated concepts have revealed the diverse role of chemokines in the biology of cancer initiation and progression. Genomic instabilities and alterations drive tumor heterogeneity, providing more options for the selection and metastatic progression to cancer cells. Tumor heterogeneity and acquired drug resistance are the main obstacles in managing cancer therapy and the primary root cause of metastasis. Studies emphasize that multiple chemokine/receptor axis are involved in cancer cell-mediated organ-specific distant metastasis. One of the persuasive mechanisms for heterogeneity and subsequent events is sturdily interlinked with the crosstalk between chemokines and their receptors on cancer cells and tissue-specific microenvironment. Among different metastatic niches, skeletal metastasis is frequently observed in the late stages of prostate, breast, and lung cancer and significantly reduces the survival of cancer patients. Therefore, it is crucial to elucidate the role of chemokines and their receptors in metastasis and bone remodeling. Here, we review the potential chemokine/receptor axis in tumorigenesis, tumor heterogeneity, metastasis, and vicious cycle in bone microenvironment.

Cytokines chattering in pancreatic ductal adenocarcinoma tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) consists of multiple cell types interspersed by dense fibrous stroma. These cells communicate through low molecular weight signaling molecules called cytokines. The cytokines, through their receptors, facilitate PDAC initiation, progression, metastasis, and distant colonization of malignant cells. These signaling mediators secreted from tumor-associated macrophages, and cancer-associated fibroblasts in conjunction with oncogenic Kras mutation initiate acinar to ductal metaplasia (ADM), resulting in the appearance of early preneoplastic lesions. Further, M1- and M2-polarized macrophages provide proinflammatory conditions and promote deposition of extracellular matrix, whereas myofibroblasts and T-lymphocytes, such as Th17 and T-regulatory cells, create a fibroinflammatory and immunosuppressive environment with a significantly reduced cytotoxic T-cell population. During PDAC progression, cytokines regulate the expression of various oncogenic regulators such as NFκB, c-myc, growth factor receptors, and mucins resulting in the formation of high-grade PanIN lesions, epithelial to mesenchymal transition, invasion, and extravasation of malignant cells, and metastasis. During metastasis, PDAC cells colonize at the premetastatic niche created in the liver, and lung, an organotropic function primarily executed by cytokines in circulation or loaded in the exosomes from the primary tumor cells. The indispensable contribution of these cytokines at every stage of PDAC tumorigenesis makes them exciting candidates in combination with immune-, chemo- and targeted radiation therapy.

Emerging role of chemokines in small cell lung cancer: Road signs for metastasis, heterogeneity, and immune response.

Small cell lung cancer (SCLC) is a recalcitrant, relatively immune-cold, and deadly subtype of lung cancer. SCLC has been viewed as a single or homogenous disease that includes deletion or inactivation of the two major tumor suppressor genes (TP53 and RB1) as a key hallmark. However, recent sightings suggest the complexity of SCLC tumors that comprises highly dynamic multiple subtypes contributing to high intratumor heterogeneity. Furthermore, the absence of targeted therapies, the understudied tumor immune microenvironment (TIME), and subtype plasticity are also responsible for therapy resistance. Secretory chemokines play a crucial role in immunomodulation by trafficking immune cells to the tumors. Chemokines and cytokines modulate the anti-tumor immune response and wield a pro-/anti-tumorigenic effect on SCLC cells after binding to cognate receptors. In this review, we summarize and highlight recent findings that establish the role of chemokines in SCLC growth and metastasis, and sophisticated intratumor heterogeneity. We also discuss the chemokine networks that are putative targets or modulators for augmenting the anti-tumor immune responses in targeted or chemo-/immuno-therapeutic strategies, and how these combinations may be utilized to conquer SCLC.

Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis.

Chemokines are recognized as the major contributor to various tumorigenesis, tumor heterogeneity, and failures of current cancer therapies. The tumor microenvironment (TME) is enriched with chemokines and cytokines and plays a pivotal role in cancer progression. Chronic inflammation is also considered an instructive process of cancer progression, where chemokines are spatiotemporally secreted by malignant cells and leukocyte subtypes that initiate cell trafficking into the TME. In various cancers, prostate cancer (PCa) is reported as one of the leading cancers in the worldwide male population. The chemokines-mediated signaling pathways are intensively involved in PCa progression and metastasis. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance. Chemokine's system and immune cells represent a promising target to suppress tumorigenic environments and serve as potential therapy/immunotherapy for the PCa. In this review, an attempt has been made to shed light on the alteration of chemokine and cytokine profiles during PCa progression and metastasis. We also discussed the recent findings of the diverse molecular signaling of these circulating chemokines and their corresponding receptors that could become future targets for therapeutic management of PCa.

Chemokine-mucinome interplay in shaping the heterogeneous tumor microenvironment of pancreatic cancer.

Pancreatic cancer (PC) is exemplified by a complex immune-suppressive, fibrotic tumor microenvironment (TME), and aberrant expression of mucins. The constant crosstalk between cancer cells, cancer-associated fibroblasts (CAFs), and the immune cells mediated by the soluble factors and inflammatory mediators including cytokines, chemokines, reactive oxygen species (ROS) promote the dynamic temporal switch towards an immune-escape phenotype in the neoplastic cells and its microenvironment that bolsters disease progression. Chemokines have been studied in PC pathogenesis, albeit poorly in the context of mucins, tumor glycocalyx, and TME heterogeneity (CAFs and immune cells). With correlative analysis from PC patients' transcriptome data, support from available literature, and scientific arguments-based speculative extrapolations in terms of disease pathogenesis, we have summarized in this review a comprehensive understanding of chemokine-mucinome interplay during stromal modulation and immune-suppression in PC. Future studies should focus on deciphering the complexities of chemokine-mediated control of glycocalyx maturation, immune infiltration, and CAF-associated immune suppression. Knowledge extracted from such studies will be beneficial to mechanistically correlate the mucin-chemokine abundance in serum versus pancreatic tumors of patients, which may aid in prognostication and stratification of PC patients for immunotherapy.

Immune checkpoint blockade in pancreatic cancer: Trudging through the immune desert.

Pancreatic cancer (PC) has exceptionally high mortality due to ineffective treatment strategies. Immunotherapy, which mobilizes the immune system to fight against cancer, has been proven successful in multiple cancers; however, its application in PC has met with limited success. In this review, we articulated that the pancreatic tumor microenvironment is immuno-suppressive with extensive infiltration by M2-macrophages and myeloid-derived suppressive cells but low numbers of cytotoxic T-cells. In addition, low mutational load and poor antigen processing, presentation, and recognition contribute to the limited response to immunotherapy in PC. Immune checkpoints, the critical targets for immunotherapy, have high expression in PC and stromal cells, regulated by tumor microenvironmental milieu (cytokine and metabolites) and cell-intrinsic mechanisms (epigenetic regulation, oncogenic signaling, and post-translational modifications). Combining immunotherapy with modulators of the tumor microenvironment may facilitate the development of novel therapeutic regimens to manage PC.

Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease.

Small cell lung cancer (SCLC) is a particular subtype of lung cancer with high mortality. Recent advances in understanding SCLC genomics and breakthroughs of immunotherapy have substantially expanded existing knowledge and treatment modalities. However, challenges associated with SCLC remain enigmatic and elusive. Most of the conventional drug discovery approaches targeting altered signaling pathways in SCLC end up in the 'grave-yard of drug discovery', which mandates exploring novel approaches beyond inhibiting cell signaling pathways. Epigenetic modifications have long been documented as the key contributors to the tumorigenesis of almost all types of cancer, including SCLC. The last decade witnessed an exponential increase in our understanding of epigenetic modifications for SCLC. The present review highlights the central role of epigenetic regulations in acquiring neoplastic phenotype, metastasis, aggressiveness, resistance to chemotherapy, and immunotherapeutic approaches of SCLC. Different types of epigenetic modifications (DNA/histone methylation or acetylation) that can serve as predictive biomarkers for prognostication, treatment stratification, neuroendocrine lineage determination, and development of potential SCLC therapies are also discussed. We also review the utility of epigenetic targets/epidrugs in combination with first-line chemotherapy and immunotherapy that are currently under investigation in preclinical and clinical studies. Altogether, the information presents the inclusive landscape of SCLC epigenetics and epidrugs that will help to improve SCLC outcomes.

Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications.

Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.

MUC16 promotes triple-negative breast cancer lung metastasis by modulating RNA-binding protein ELAVL1/HUR.

BACKGROUND: Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. METHODS: The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. RESULTS: MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. CONCLUSIONS: Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma.

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.

Immunotherapy: an emerging modality to checkmate brain metastasis.

The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.