The Intricate Balance between Life and Death: ROS, Cathepsins, and Their Interplay in Cell Death and Autophagy.

Cellular survival hinges on a delicate balance between accumulating damages and repair mechanisms. In this intricate equilibrium, oxidants, currently considered physiological molecules, can compromise vital cellular components, ultimately triggering cell death. On the other hand, cells possess countermeasures, such as autophagy, which degrades and recycles damaged molecules and organelles, restoring homeostasis. Lysosomes and their enzymatic arsenal, including cathepsins, play critical roles in this balance, influencing the cell's fate toward either apoptosis and other mechanisms of regulated cell death or autophagy. However, the interplay between reactive oxygen species (ROS) and cathepsins in these life-or-death pathways transcends a simple cause-and-effect relationship. These elements directly and indirectly influence each other's activities, creating a complex web of interactions. This review delves into the inner workings of regulated cell death and autophagy, highlighting the pivotal role of ROS and cathepsins in these pathways and their intricate interplay.

Biomimetic approaches for targeting tumor-promoting inflammation.

With the ultimate goal of increasing tumor accumulation of therapeutics, various nanocarriers have been designed to overcome biological barriers encountered at each stage, from drug administration to the cancerous lesion. Stabilizing circulation and functionalization of the targeting surface impart high tumor accumulation properties to nanocarriers. However, various cells can recognize and infiltrate the tumor microenvironment more efficiently than synthetic carriers via overexpression of adhesive ligands, particularly in inflamed stroma of tumors. Thus, a new field of nanomedicine, called biomimicry, has evolved to generate nanoparticles with the same biological characteristics as cells that naturally infiltrate tumors. Revolutionary synthetic processes have been developed to transfer the cell membrane of leukocytes and mesenchymal cells to synthetic carriers. In addition, cells can generate their own "nanocarriers," known as exosomes, to transport molecular messages to distant sites, while biomimicry of viral and bacterial agents allows high targeting efficiency towards inflammatory immune cells. Alterations in the protein expression in cancer cells caused by inflammation can also be exploited for drug delivery. Finally, new developments in biomimetic drug delivery focus on turning the infiltrating cells into microcarriers that can actively perfuse the tumor and eventually release their therapeutic payload. In this review, we summarize recent developments in biomimetic drug delivery with a particular focus on targeting the tumor inflammatory microenvironment.

Expression, Intracellular Localization, and Maturation of Cysteine Cathepsins in Renal Embryonic and Cancer Cell Lines.

Cysteine cathepsins play an important role in tumor development and metastasis. The expression of these enzymes is often increased in many types of tumor cells. Cysteine cathepsins contribute to carcinogenesis through a number of mechanisms, including proteolysis of extracellular matrix and signaling molecules on the cell surface, as well as degradation of transcription factors and disruption of signaling cascades in the cell nucleus. Distinct oncogenic functions have been reported for several members of the cysteine cathepsin family in various types of cancer, but a comparative study of all eleven cysteine cathepsins in one experimental model is still missing. In this work, we assessed and compared the expression, localization, and maturation of all eleven cysteine cathepsins in embryonic kidney cells HEK293 and kidney cancer cell lines 769-P and A-498. We found that the expression of cathepsins V, B, Z, L, and S was 3- to 9-fold higher in kidney tumor cells than in embryonic cells. We also showed that all cysteine cathepsins were present in varying amounts in the nucleus of both embryonic and tumor cells. Notably, more than half of the cathepsin Z or K and over 88% of cathepsin F were localized in tumor cell nuclei. Moreover, mature forms of cysteine cathepsins were more prevalent in tumor cells than in embryonic cells. These results can be further used to develop novel diagnostic tools and may assist in the investigation of cysteine cathepsins as potential therapeutic targets.

Anticancer Nanotherapeutics in Clinical Trials: The Work behind Clinical Translation of Nanomedicine.

The ultimate goal of nanomedicine has always been the generation of translational technologies that can ameliorate current therapies. Cancer disease represented the primary target of nanotechnology applied to medicine, since its clinical management is characterized by very toxic therapeutics. In this effort, nanomedicine showed the potential to improve the targeting of different drugs by improving their pharmacokinetics properties and to provide the means to generate new concept of treatments based on physical treatments and biologics. In this review, we considered different platforms that reached the clinical trial investigation, providing an objective analysis about their physical and chemical properties and the working mechanism at the basis of their tumoritr opic properties. With this review, we aim to help other scientists in the field in conceiving their delivering platforms for clinical translation by providing solid examples of technologies that eventually were tested and sometimes approved for human therapy.

Thin Thermoresponsive Polymer Films for Cell Culture: Elucidating an Unexpected Thermal Phase Behavior by Atomic Force Microscopy.

Application of poly-N-isopropylacrylamide (PNIPAM) and its more hydrophobic copolymers with N-tert-butylacrylamide (NtBA) as supports for cell sheets has been validated in numerous studies. The binary systems of these polymers with water are characterized by a lower critical solution temperature (LCST) in a physiologically favorable region. Upon lowering the temperature below the LCST, PNIPAM chains undergo a globule-to-coil transition, causing the film dissolution and cell sheet detachment. The character of the PNIPAM-water miscibility behavior is rather complex and not completely understood. Here, we applied atomic force microscopy to track the phase transition in thin films of linear thermoresponsive (co)polymers (PNIPAM and PNIPAM-co-NtBA) prepared by spin-coating. We studied the films' Young's modulus, roughness, and thickness in air and in distilled water in a full thermal cycle. In dry films, in the absence of water, all the measured parameters remained invariant. The swollen films in water above the LCST were softer by 2-3 orders of magnitude and about 10 times rougher than the corresponding dry films. Upon lowering the temperature to the LCST, the films passed through the phase transition observed as a drastic drop of Young's modulus (about an order of magnitude) and decrease in roughness in both polymers in a narrow temperature range. However, the films did not lose their integrity and demonstrated almost fully reversible changes in the mechanical properties and roughness. The thermal dependence of the films' thickness confirmed that they dissolved only partially and required an external force to induce the complete destruction. The reversible thermal behavior which is generally not expected from non-cross-linked polymers is a key finding, especially with respect to their practical application in cell culture. Both the thermodynamic and kinetic factors, as well as the confinement effect, may be responsible for this peculiar film robustness, which requires overcooling and the aid of an external force to destroy the film.

Anaerotalea alkaliphila gen. nov., sp. nov., an alkaliphilic, anaerobic, fermentative bacterium isolated from a terrestrial mud volcano.

Diversity of extremophilic microorganisms in mud volcanoes is largely unexplored. Here, we report the isolation of a novel alkaliphilic, mesophilic, fermentative bacterium (strain F-3apT) from a terrestrial mud volcano located at the Taman peninsula, Russia. Cells of strain F-3apT are Gram-stain-positive non-motile rods. The formation of endospores is not observed. The temperature range for growth is 14-42 °C, with an optimum at 37 °C. The pH range for growth is 7.5-11.0, with an optimum at pH 9.0. The isolate utilizes various organic polymeric substances, organic acids, carbohydrates, and proteinaceous compounds. The end products of glucose fermentation are ethanol, CO2, and H2. The major cellular fatty acids of strain F-3apT are C16:0, C16:1, and C14:0. Phylogenetic analysis reveals that strain F-3apT belongs to the order Clostridiales, with less than 91% of 16S rRNA gene sequence similarity to any species with a validly published name. The total size of the genome of strain F-3apT is 2.98 Mb, and a genomic DNA G + C content is 56.78 mol%. The whole-genome phylogenetic analysis confirms that strain F-3apT forms a distinct lineage within Clostridia. We propose to assign strain F-3apT to a new species of a novel genus Anaerotalea alkaliphila gen. nov., sp. nov. The type strain is F-3apT (= KCTC 15917 T = VKM B-3406 T).

A Collagen Basketweave from the Giant Squid Mantle as a Robust Scaffold for Tissue Engineering.

The growing applications of tissue engineering technologies warrant the search and development of biocompatible materials with an appropriate strength and elastic moduli. Here, we have extensively studied a collagenous membrane (GSCM) separated from the mantle of the Giant squid Dosidicus Gigas in order to test its potential applicability in regenerative medicine. To establish the composition and structure of the studied material, we analyzed the GSCM by a variety of techniques, including amino acid analysis, SDS-PAGE, and FTIR. It has been shown that collagen is a main component of the GSCM. The morphology study by different microscopic techniques from nano- to microscale revealed a peculiar packing of collagen fibers forming laminae oriented at 60-90 degrees in respect to each other, which, in turn, formed layers with the thickness of several microns (a basketweave motif). The macro- and micromechanical studies showed high values of the Young's modulus and tensile strength. No significant cytotoxicity of the studied material was found by the cytotoxicity assay. Thus, the GSCM consists of a reinforced collagen network, has high mechanical characteristics, and is non-toxic, which makes it a good candidate for the creation of a scaffold material for tissue engineering.

Evaluation of Supercritical CO2-Assisted Protocols in a Model of Ovine Aortic Root Decellularization.

One of the leading trends in the modern tissue engineering is the development of new effective methods of decellularization aimed at the removal of cellular components from a donor tissue, reducing its immunogenicity and the risk of rejection. Supercritical CO2 (scCO2)-assisted processing has been proposed to improve the outcome of decellularization, reduce contamination and time costs. The resulting products can serve as personalized tools for tissue-engineering therapy of various somatic pathologies. However, the decellularization of heterogeneous 3D structures, such as the aortic root, requires optimization of the parameters, including preconditioning medium composition, the type of co-solvent, values of pressure and temperature inside the scCO2 reactor, etc. In our work, using an ovine aortic root model, we performed a comparative analysis of the effectiveness of decellularization approaches based on various combinations of these parameters. The protocols were based on the combinations of treatments in alkaline, ethanol or detergent solutions with scCO2-assisted processing at different modes. Histological analysis demonstrated favorable effects of the preconditioning in a detergent solution. Following processing in scCO2 medium provided a high decellularization degree, reduced cytotoxicity, and increased ultimate tensile strength and Young's modulus of the aortic valve leaflets, while the integrity of the extracellular matrix was preserved.

Collagen fibrillar structures in vocal fold scarring and repair using stem cell therapy: a detailed histological, immunohistochemical and atomic force microscopy study.

Regenerative medicine opens new opportunities in the repair of cicatricial lesions of the vocal folds. Here, we present a thorough morphological study, with the focus on the collagen structures in the mucosa of the vocal folds, dedicated to the effects of stem cells on the vocal folds repair after cicatricial lesions. We used a conventional experimental model of a mature scar of the rabbit vocal folds, which was surgically excised with a simultaneous implantation of autologous bone marrow-derived mesenchymal stem cells (MSC) into the defect. The restoration of the vocal folds was studied 3 months postimplantation of stem cells and 6 months after the first surgery. The collagen structure assessment included histology, immunohistochemistry and atomic force microscopy (AFM) studies. According to the data of optical microscopy and AFM, as well as to immunohistochemical analysis, MSC implantation into the vocal fold defect leads not only to the general reduction of scarring, normal ratio of collagens type I and type III, but also to a more complete restoration of architecture and ultrastructure of collagen fibres in the mucosa, as compared to the control. The collagen structures in the scar tissue in the vocal folds with implanted MSC are more similar to those in the normal mucosa of the vocal folds than to those of the untreated scars. AFM has proven to be an instrumental technique in the assessment of the ultrastructure restoration in such studies. LAY DESCRIPTION: Regenerative medicine opens new opportunities in the repair of the vocal fold scars. Because collagen is a main component in the vocal fold mucosa responsible for the scar formation and repair, we focus on the collagen structures in the mucosa of the vocal folds, using a thorough morphological study based on histology and atomic force microscopy (AFM). Atomic force microscopy is a scanning microscopic technique which allows revealing the internal structure of a tissue with a resolution up to nanometres. We used a conventional experimental model of a mature scar of the rabbit vocal folds, surgically excised and treated with a mesenchymal stem cells transplant. Our morphological study, primarily AFM, explicitly shows that the collagen structures in the scarred vocal folds almost completely restore after the stem cell treatment. Thus, the modern microscopic methods, and especially AFM are instrumental tools for monitoring the repair of the vocal folds scars.

Data from Russian Help to Determine in Which Languages the Possible Word Constraint Applies.

The Possible Word Constraint, or PWC, is a speech segmentation principle prohibiting to postulate word boundaries if a remaining segment contains only consonants. The PWC was initially formulated for English where all words contain a vowel and claimed to hold universally after being confirmed for various other languages. However, it is crucial to look at languages that allow for words without vowels. Two such languages have been tested: data from Slovak were compatible with the PWC, while data from Tarifiyt Berber did not support it. We hypothesize that the fixed word stress could influence the results in Slovak and report two word-spotting experiments on Russian, which has similar one-consonant words, but flexible word stress. The results contradict the PWC, so we suggest that it does not operate in the languages where words without vowels are possible, while the results from Slovak might be explained by its prosodic properties.

Breast Cancer Immune Landscape: Interplay Between Systemic and Local Immunity.

Breast cancer (BC) is one of the most common malignancies in women worldwide. Numerous studies in immuno-oncology and successful trials of immunotherapy have demonstrated the causal role of the immune system in cancer pathogenesis. The interaction between the tumor and the immune system is known to have a dual nature. Despite cytotoxic lymphocyte activity against transformed cells, a tumor can escape immune surveillance and leverage chronic inflammation to maintain its own development. Research on antitumor immunity primarily focuses on the role of the tumor microenvironment, whereas the systemic immune response beyond the tumor site is described less thoroughly. Here, a comprehensive review of the formation of the immune profile in breast cancer patients is offered. The interplay between systemic and local immune reactions as self-sustaining mechanism of tumor progression is described and the functional activity of the main cell populations related to innate and adaptive immunity is discussed. Additionally, the interaction between different functional levels of the immune system and their contribution to the development of the pro- or anti-tumor immune response in BC is highlighted. The presented data can potentially inform the development of new immunotherapy strategies in the treatment of patients with BC.

Swelling, Rupture and Endosomal Escape of Biological Nanoparticles Per Se and Those Fused with Liposomes in Acidic Environment.

Biological nanoparticles (NPs), such as extracellular vesicles (EVs), exosome-mimetic nanovesicles (EMNVs) and nanoghosts (NGs), are perspective non-viral delivery vehicles for all types of therapeutic cargo. Biological NPs are renowned for their exceptional biocompatibility and safety, alongside their ease of functionalization, but a significant challenge arises when attempting to load therapeutic payloads, such as nucleic acids (NAs). One effective strategy involves fusing biological NPs with liposomes loaded with NAs, resulting in hybrid carriers that offer the benefits of both biological NPs and the capacity for high cargo loads. Despite their unique parameters, one of the major issues of virtually any nanoformulation is the ability to escape degradation in the compartment of endosomes and lysosomes which determines the overall efficiency of nanotherapeutics. In this study, we fabricated all major types of biological and hybrid NPs and studied their response to the acidic environment observed in the endolysosomal compartment. In this study, we show that EMNVs display increased protonation and swelling relative to EVs and NGs in an acidic environment. Furthermore, the hybrid NPs exhibit an even greater response compared to EMNVs. Short-term incubation of EMNVs in acidic pH corresponding to late endosomes and lysosomes again induces protonation and swelling, whereas hybrid NPs are ruptured, resulting in the decline in their quantities. Our findings demonstrate that in an acidic environment, there is enhanced rupture and release of vesicular cargo observed in hybrid EMNVs that are fused with liposomes compared to EMNVs alone. This was confirmed through PAGE electrophoresis analysis of mCherry protein loaded into nanoparticles. In vitro analysis of NPs colocalization with lysosomes in HepG2 cells demonstrated that EMNVs mostly avoid the endolysosomal compartment, whereas hybrid NPs escape it over time. To conclude, (1) hybrid biological NPs fused with liposomes appear more efficient in the endolysosomal escape via the mechanism of proton sponge-associated scavenging of protons by NPs, influx of counterions and water, and rupture of endo/lysosomes, but (2) EMNVs are much more efficient than hybrid NPs in actually avoiding the endolysosomal compartment in human cells. These results reveal biochemical differences across four major types of biological and hybrid NPs and indicate that EMNVs are more efficient in escaping or avoiding the endolysosomal compartment.

Phase transition and potential biomedical applications of thermoresponsive compositions based on polysaccharides, proteins and DNA: A review.

Smart thermoresponsive polymers have long attracted attention as materials of a great potential for biomedical applications, mainly for drug delivery, tissue engineering and wound dressing, with a special interest to injectable hydrogels. Poly-N-isopropylacrylamide (PNIPAM) is the most important synthetic thermoresponsive polymer due to its physiologically relevant transition temperature. However, the use of unmodified PNIPAM encounters such problems as low biodegradability, low drug loading capacity, slow response to thermal stimuli, and insufficient mechanical robustness. The use of natural polysaccharides and proteins in combinations with PNIPAM, in the form of grafted copolymers, IPNs, microgels and physical mixtures, is aimed at overcoming these drawbacks and creating dual-functional materials with both synthetic and natural polymers' properties. When developing such compositions, special attention should be paid to preserving their key property, thermoresponsiveness. Addition of hydrophobic and hydrophilic fragments to PNIPAM is known to affect its transition temperature. This review covers various classes of natural polymers - polysaccharides, fibrous and non-fibrous proteins, DNA - used in combination with PNIPAM for the prospective biomedical purposes, with a focus on their phase transition temperatures and its relation to the natural polymer's structure.

New Perspectives on the Role of Nuclear Proteases in Cell Death Pathways.

Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, others remain poorly characterized. Regulation of nuclear protease activity is a promising therapeutic strategy that could selectively induce favorable cell death pathways in specific tissues or organs. Thus, by understanding the roles of newly discovered or predicted nuclear proteases in cell death processes, we can identify new pharmacological targets for improving therapeutic outcomes. In this article, we delved into the role of nuclear proteases in several types of cell death and explore potential avenues for future research and therapeutic development.

Prolonged and Controllable Release of Doxorubicin Hydrochloride from the Composite Electrospun Poly(ε-Caprolactone)/Polyvinylpyrrolidone Scaffolds.

Burst release, typical for the drug-loaded electrospun poly(ε-caprolactone) (PCL) scaffolds is unfavorable in case of cytostatics due to the toxic levels reached during the initial implantation period. In the present short communication, we report an unexpected ability of the composite scaffolds made of PCL and water-soluble polyvinylpyrrolidone (PVP) to provide long-term release of widely used anti-cancer drug doxorubicin hydrochloride (DOX-HCl). That effect was observed for electrospun DOX-HCl-loaded composite scaffolds based on PCL and PVP with various mass ratios (100/0, 95/5, 90/10, 75/25 and 50/50). After the morphology and water contact angle studies, it was concluded that PVP content has no effect on the average fiber diameter, while PVP content higher 10 wt. % changes the hydrophobic character of the scaffolds surface (water contact angle of 123.9 ± 3.5°) to superhydrophilic (water contact angle of 0°). Despite the dramatic change in water wettability, by high performance liquid chromatography (HPLC), it was revealed that the PVP content in the scaffolds reduces the DOX-HCl release rate under short (first hours) and long-term (during 1 month) exposure to phosphate buffer saline (PBS). These results are in good agreement with in vitro studies, in which the viability of HeLa cervical cancer cells was higher after 24 h of culture with scaffolds with high PVP content.

Electrospun Poly-L-Lactic Acid Scaffolds Surface-Modified via Reactive Magnetron Sputtering Using Different Mixing Ratios of Nitrogen and Xenon.

Controlled regeneration processes involving tissue growth using the surface and structure of scaffolds, are actively used in tissue engineering. Reactive magnetron sputtering is a versatile surface modification method of both metal and polymer substrates, as the properties of the formed coatings can be modified in a wide range by changing the process parameters. In magnetron sputtering, the working gas and its composition have an influence on the chemical composition and physical characteristics of the obtained coatings. However, there are no studies addressing the influence of the nitrogen/xenon gas mixture ratio in direct current magnetron sputtering on the deposition rate, physicochemical and in vitro properties of surface-modified biocompatible poly-L-lactic acid scaffolds. In this study, the application of mixtures of nitrogen and xenon in various ratios is demonstrated to modify the surface of non-woven poly-L-lactic acid scaffolds by direct current magnetron sputtering of a titanium target. It has been found that the magnetron sputtering parameters chosen do not negatively influence the morphology of the prepared scaffolds, but increase the hydrophilicity. Moreover, quantitative spectroscopic analysis results indicate that the formed coatings are primarily composed of titanium oxide and titanium oxynitride compounds and is dependent on the gas mixture ratio only to a certain extent. Atomic force microscopy investigations of the roughness of the fibers of the electrospun scaffolds and the thickness of the coatings formed on them show that the considerable variations observed in the intrinsic fiber reliefs are due to the formation of a fine layer on the fiber surfaces. The observed decrease in roughness after plasma modification is due to temperature and radiation effects of the plasma. In vitro experiments with human osteosarcoma cells show that the scaffolds investigated here have no cytotoxic effect on these cells. The cells adhere and proliferate well on each of the surface-modified electrospun scaffolds, with stimulation of cell differentiation in the osteogenic direction.

The cell softening as a universal indicator of cell damage during cytotoxic effects.

Cytotoxicity assays are essential tests in studies on the safety and biocompatibility of various substances and on the efficiency of anticancer drugs. The most frequently used assays commonly require application of externally added labels and read only collective response of cells. Recent studies show that the internal biophysical parameters of cells can be associated with the cellular damage. Therefore, using atomic force microscopy, we assessed the changes in the viscoelastic parameters of cells treated with eight different common cytotoxic agents to gain a more systematic view of the occurring mechanical changes. With the robust statistical analysis to account for both the cell-level variability and the experimental reproducibility, we have found that cell softening is a common response after each treatment. More precisely, the combined changes in the viscoelastic parameters of power-law rheology model led to a significant decrease of the apparent elastic modulus. The comparison with the morphological parameters (cytoskeleton and cell shape) demonstrated a higher sensitivity of the mechanical parameters versus the morphological ones. The obtained results support the idea of cell mechanics-based cytotoxicity tests and suggest a common way of a cell responding to damaging actions by softening.

Hydroxychloroquine Enhances Cytotoxic Properties of Extracellular Vesicles and Extracellular Vesicle-Mimetic Nanovesicles Loaded with Chemotherapeutics.

Because of their high biocompatibility, biological barrier negotiation, and functionalization properties, biological nanoparticles have been actively investigated for many medical applications. Biological nanoparticles, including natural extracellular vesicles (EVs) and synthetic extracellular vesicle-mimetic nanovesicles (EMNVs), represent novel drug delivery vehicles that can accommodate different payloads. In this study, we investigated the physical, biological, and delivery properties of EVs and EMNVs and analyzed their ability to deliver the chemotherapeutic drug doxorubicin. EMNVs and EVs exhibit similar properties, but EMNVs are more effectively internalized, while EVs show higher intracellular doxorubicin release activity. In addition, these nanotherapeutics were investigated in combination with the FDA-approved drug hydroxychloroquine (HCQ). We demonstrate that HCQ-induced lysosome destabilization and could significantly increase nanoparticle internalization, doxorubicin release, and cytotoxicity. Altogether, these data demonstrate that, from the delivery standpoint in vitro, the internalization of EMNVs and EVs and their payload release were slightly different and both nanotherapeutics had comparable cytotoxic performance. However, the synthesis of EMNVs was significantly faster and cost-effective. In addition, we highlight the benefits of combining biological nanoparticles with the lysosome-destabilizing agent HCQ that increased both the internalization and the cytotoxic properties of the particles.

Monocyte programming by cancer therapy.

Monocytes in peripheral blood circulation are the precursor of essential cells that control tumor progression, that include tumor-associated macrophages (TAMs), dendritic cells (DCs) and myeloid-derive suppressor cells (MDSC). Monocytes-derived cells orchestrate immune reactions in tumor microenvironment that control disease outcome and efficiency of cancer therapy. Four major types of anti-cancer therapy, surgery, radiotherapy, chemotherapy, and most recent immunotherapy, affect tumor-associated macrophage (TAM) polarization and functions. TAMs can also decrease the efficiency of therapy in a tumor-specific way. Monocytes is a major source of TAMs, and are recruited to tumor mass from the blood circulation. However, the mechanisms of monocyte programming in circulation by different therapeutic onsets are only emerging. In our review, we present the state-of-the art about the effects of anti-cancer therapy on monocyte progenitors and their dedifferentiation, on the content of monocyte subpopulations and their transcriptional programs in the circulation, on their recruitment into tumor mass and their potential to give origin for TAMs in tumor-specific microenvironment. We have also summarized very limited available knowledge about genetics that can affect monocyte interaction with cancer therapy, and highlighted the perspectives for the therapeutic targeting of circulating monocytes in cancer patients. We summarized the knowledge about the mediators that affect monocytes fate in all four types of therapies, and we highlighted the perspectives for targeting monocytes to develop combined and minimally invasive anti-cancer therapeutic approaches.