The Proteolytic Landscape of Ovarian Cancer: Applications in Nanomedicine

Ovarian cancer (OvCa) is one of the leading causes of mortality globally with an overall 5-year survival of 47%. The predominant subtype of OvCa is epithelial carcinoma, which can be highly aggressive. This review launches with a summary of the clinical features of OvCa, including staging and current techniques for diagnosis and therapy. Further, the important role of proteases in OvCa progression and dissemination is described. Proteases contribute to tumor angiogenesis, remodeling of extracellular matrix, migration and invasion, major processes in OvCa pathology. Multiple proteases, such as metalloproteinases, trypsin, cathepsin and others, are overexpressed in the tumor tissue. Presence of these catabolic enzymes in OvCa tissue can be exploited for improving early diagnosis and therapeutic options in advanced cases. Nanomedicine, being on the interface of molecular and cellular scales, can be designed to be activated by proteases in the OvCa microenvironment. Various types of protease-enabled nanomedicines are described and the studies that focus on their diagnostic, therapeutic and theranostic potential are reviewed.     

Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment

Triple-negative breast cancer (TNBC) is defined based on the absence of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Currently, chemotherapy is the major therapeutic approach for TNBC patients; however, poor prognosis after a standard chemotherapy regimen is still commonplace due to drug resistance. Abnormal tumor metabolism and infiltrated immune or stromal cells in the tumor microenvironment (TME) may orchestrate mammary tumor growth and metastasis or give rise to new subsets of cancer cells resistant to drug treatment. The immunosuppressive mechanisms established in the TME make cancer cell clones invulnerable to immune recognition and killing, and turn immune cells into tumor-supporting cells, hence allowing cancer growth and dissemination. Phytochemicals with the potential to change the tumor metabolism or reprogram the TME may provide opportunities to suppress cancer metastasis and/or overcome chemoresistance. Furthermore, phytochemical intervention that reprograms the TME away from favoring immunoevasion and instead towards immunosurveillance may prevent TNBC metastasis and help improve the efficacy of combination therapies as phyto-adjuvants to combat drug-resistant TNBC. In this review, we summarize current findings on selected bioactive plant-derived natural products in preclinical mouse models and/or clinical trials with focus on their immunomodulatory mechanisms in the TME and their roles in regulating tumor metabolism for TNBC prevention or therapy.     

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.     

Calcification-Based Cancer Diagnosis and Therapy

In nature, calcium deposition is a common biological process in mammals that shapes mechanical structures and creates the functions of bones and teeth, and causes calculi formation. Spontaneous tumor calcification and regional lymph node calcification in colorectal cancer, lung cancer, and glioblastoma have been proven to be benign prognostic factors in the clinic. In line with this concept, we introduce the idea and lead the compound development of artificially inducing bionic calcification around the surface of cancer cells. This process is shown to have excellent effects in the inhibition of growth and metastases of cervical, breast, and lung tumors, as well as superb performance in early-stage diagnosis. Therefore, we predict that this concept may open the door for cancer targeting calcification therapy and diagnosis and provide an outlook for a new avenue in anticancer drug development.     

Role of miRNA-19a in Cancer Diagnosis and Poor Prognosis

Cancer is a multifactorial disease that affects millions of people every year and is one of the most common causes of death in the world. The high mortality rate is very often linked to late diagnosis; in fact, nowadays there are a lack of efficient and specific markers for the early diagnosis and prognosis of cancer. In recent years, the discovery of new diagnostic markers, including microRNAs (miRNAs), has been an important turning point for cancer research. miRNAs are small, endogenous, non-coding RNAs that regulate gene expression. Compelling evidence has showed that many miRNAs are aberrantly expressed in human carcinomas and can act with either tumor-promoting or tumor-suppressing functions. miR-19a is one of the most investigated miRNAs, whose dysregulated expression is involved in different types of tumors and has been potentially associated with the prognosis of cancer patients. The aim of this review is to investigate the role of miR-19a in cancer, highlighting its involvement in cell proliferation, cell growth, cell death, tissue invasion and migration, as well as in angiogenesis. On these bases, miR-19a could prove to be truly useful as a potential diagnostic, prognostic, and therapeutic marker.     

Skeletal Muscle–Adipose Tissue–Tumor Axis: Molecular Mechanisms Linking Exercise Training in Prostate Cancer

Increased visceral adiposity may influence the development of prostate cancer (PCa) aggressive tumors and cancer mortality. White adipose tissue (WAT), usually referred to as periprostatic adipose tissue (PPAT), surrounds the prostatic gland and has emerged as a potential mediator of the tumor microenvironment. Exercise training (ET) induces several adaptations in both skeletal muscle and WAT. Some of these effects are mediated by ET-induced synthesis and secretion of several proteins, known as myo- and adipokines. Together, myokines and adipokines may act in an endocrine-like manner to favor communication between skeletal muscle and WAT, as they may work together to improve whole-body metabolic health. This crosstalk may constitute a potential mechanism by which ET exerts its beneficial role in the prevention and treatment of PCa-related disorders; however, this has not yet been explored. Therefore, we reviewed the current evidence on the effects of skeletal muscle–WAT–tumor crosstalk in PCa, and the potential mediators of this process to provide a better understanding of underlying ET-related mechanisms in cancer.     

Cell Component and Function of Tumor Microenvironment in Thyroid Cancer

Thyroid cancer is the most common cancer in the endocrine system. Most thyroid cancers have good prognosis, but some of them are resistant to treatment or show aggressive behavior. Like other tumors, thyroid cancers harbor tumor microenvironment (TME) composed of cancer associated fibroblasts (CAF) and immune cells. Autoimmune lymphocytic thyroiditis can occur in the thyroid, and it may be associated with cancer development. TME is involved in tumor progression through various mechanisms: (1) CAF is involved in tumor progression through cell proliferation and extracellular matrix (ECM) remodeling; and (2) immune cells are involved in tumor progression through cell proliferation, angiogenesis, epithelial mesenchymal transformation (EMT), and immune suppression. These events are activated by various cytokines, chemokines, and metabolites secreted from cells that comprise TME. This review is focused on how CAF and immune cells, two important cell components of thyroid cancer TME, are involved in tumor progression, and will explore their potential as therapeutic targets.     

CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.     

Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type

The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors.     

The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.     

The Ferroptosis Molecular Subtype Reveals Characteristics of the Tumor Microenvironment,Immunotherapeutic Response,and Prognosis in Gastric Cancer

Ferroptosis is a relatively new form of programmed cell death, which can enhance the efficacy of tumor immunotherapy by regulating the tumor microenvironment (TME). In the face of the dilemma of a great difference in the efficacy of immunotherapy for gastric cancer (GC) patients, the exploration of ferroptosis may assist us in predicting immunotherapy efficacy prior to treatment. The potential role of ferroptosis in TME still needs further elucidation. Based on ferroptosis-related genes (FRGs), we systematically evaluated ferroptosis molecular subtypes in gastric cancer. Additionally, the association between these molecular subtypes and the characteristics of TME was examined. A ferroptosis score was constructed to further explore the predictive efficacy of ferroptosis on the immunotherapy response in gastric cancer. There were also 32 other cancers that were evaluated. Three molecular subtypes of ferroptosis in gastric cancer were identified. The three immunophenotypes of tumor immune inflamed, immune excluded, as well as immune desert were mostly in agreement with the TME features of these three subtypes. The individual tumor genetic variation, TME characteristics, immunotherapy response, and prognosis could be assessed by a ferroptosis score. High ferroptosis scores in gastric cancer suggest stromal activation and immunosuppression. It is noted that tumors with a low ferroptosis score are characterized by extensive tumor mutations as well as an immune activation, which are associated with an enhanced immunotherapy response and an improved prognosis. This study reveals that ferroptosis plays an integral role in the regulation of the tumor immune microenvironment. The ferroptosis score may serve as an independent prognostic factor for GC and will deepen our understanding of the TME infiltration mechanisms as well as lead to more rational immunotherapy regimens.     

Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies.     

The Influence of a Stressful Microenvironment on Tumor Exosomes: A Focus on the DNA Cargo

Exosomes secreted by tumor cells, through the transport of bioactive molecules, reprogram the surroundings, building a microenvironment to support the development of the tumor. The discovery that exosomes carry genomic DNA reflecting that of the tumor cell of origin has encouraged studies to use them as non-invasive biomarkers. The exosome-mediated transfer of oncogenes suggested a new mechanism of malignant transformation that could play a role in the formation of metastases. Several studies have examined the role of tumor exosomes on the modulation of the tumor microenvironment, but relatively few have been directed to assess how stressful stimuli can influence their production and cargo. Understanding the changes in exosome loads and the production pattern of the stressed tumor cell may uncover actionable mechanisms responsible for tumor progression.     

A Novel Molecular Signature of Cancer-Associated Fibroblasts Predicts Prognosis and Immunotherapy Response in Pancreatic Cancer

Cancer-associated fibroblasts (CAFs), a prominent population of stromal cells, play a crucial role in tumor progression, prognosis, and treatment response. However, the relationship among CAF-based molecular signatures, clinical outcomes, and tumor microenvironment infiltration remains largely elusive in pancreatic cancer (PC). Here, we collected multicenter PC data and performed integrated analysis to investigate the role of CAF-related genes (CRGs) in PC. Firstly, we demonstrated that α-SMA⁺ CAFs were the most prominent stromal components and correlated with the poor survival rates of PC patients in our tissue microarrays. Then, we discriminated two diverse molecular subtypes (CAF clusters A and B) and revealed the significant differences in the tumor immune microenvironment (TME), four reported CAF subpopulations, clinical characteristics, and prognosis in PC samples. Furthermore, we analyzed their association with the immunotherapy response of PC patients. Lastly, a CRG score was constructed to predict prognosis, immunotherapy responses, and chemosensitivity in pancreatic cancer patients. In summary, these findings provide insights into further research targeting CAFs and their TME, and they pave a new road for the prognosis evaluation and individualized treatment of PC patients.     

Crosstalk between Tumor-Associated Macrophages and MicroRNAs: A Key Role in Tumor Microenvironment

As an in-depth understanding of immunotherapy continues to grow, current anticancer therapy research is increasingly focused on the tumor microenvironment (TME). MicroRNAs (miRNAs) play crucial roles in the regulation of genetic information and expression and mediate interactions between tumor cells and components in the TME, such as tumor-associated macrophages (macrophages). Macrophages are abundant in the TME, and their different polarization directions can promote or inhibit tumor growth and progression. By regulating biological behaviors, such as macrophage recruitment, infiltration, and polarization, miRNAs can affect various molecular pathways to regulate tumor progression and treatment response. In this review, we discuss in detail the effects of macrophages on tumors and the multifaceted effects of miRNAs on macrophages. We also discuss the potential clinical applications and prospects of targeted therapy based on miRNAs, novel clinical biomarkers, and drug delivery systems.     

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget’s “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.     

Natural Products with Activity against Lung Cancer: A Review Focusing on the Tumor Microenvironment

Lung cancer is one of the most prevalent malignancies worldwide. Despite the undeniable progress in lung cancer research made over the past decade, it is still the leading cause of cancer-related deaths and continues to challenge scientists and researchers engaged in searching for therapeutics and drugs. The tumor microenvironment (TME) is recognized as one of the major hallmarks of epithelial cancers, including the majority of lung cancers, and is associated with tumorigenesis, progression, invasion, and metastasis. Targeting of the TME has received increasing attention in recent years. Natural products have historically made substantial contributions to pharmacotherapy, especially for cancer. In this review, we emphasize the role of the TME and summarize the experimental proof demonstrating the antitumor effects and underlying mechanisms of natural products that target the TME. We also review the effects of natural products used in combination with anticancer agents. Moreover, we highlight nanotechnology and other materials used to enhance the effects of natural products. Overall, our hope is that this review of these natural products will encourage more thoughts and ideas on therapeutic development to benefit lung cancer patients.     

Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.     

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.