Salinomycin (SAL), a potent antibiotic initially remoted from the fermentation tradition of Streptomyces albicus, has demonstrated outstanding inhibitory and cytocidal results in opposition to a spectrum of gram-positive micro organism and coccidia species [1]. SAL inhibited the proliferation of breast most cancers stem cells, thus exhibiting a pronounced benefit over paclitaxel, a conventional chemotherapeutic agent [2]. We beforehand utilized nanoparticles to codeliver SAL with docetaxel or chloroquine (CQ), successfully concentrating on each most cancers cells and most cancers stem cells [3]. The anticancer mechanisms of SAL embrace the suppression of the Wnt and mitogen-activated protein kinase pathways [4], [5], the power to affect autophagy [6], decreased adenosine triphosphate (ATP) ranges [7], and the activation of endoplasmic reticulum (ER) stress [8], [9]. Though the anticancer mechanisms of SAL have been extensively investigated, the position of SAL in modulating tumor immunogenicity has not been extensively explored.
The tumor microenvironment (TME) is a posh community of assorted cells and cytokines that may drive tumor malignancy and resistance to remedies. Analysis on the influence of SAL on immune cells within the TME is rising however incomplete [10], [11]. The affect of the TME on most cancers therapy necessitates a deeper understanding of the results of SAL, which is at present restricted, particularly in regards to the immune system. There’s a clear want for extra targeted analysis to discover the potential of SAL to change the TME and enhance therapeutic outcomes. Autophagy, a elementary mobile course of, is crucial for sustaining mobile and tissue homeostasis and performs a pivotal position in most cancers remedy. It’s instrumental in modulating the TME and shaping the immune response [12]. This course of recycles mobile elements, thereby sustaining metabolic homeostasis and enabling cells to resist dietary stress. The inhibition of autophagy in tumor cells can induce oxidative stress and will result in immunogenic cell dying (ICD), which is a promising avenue for therapeutic exploitation [13]. Moreover, it enhances antigen presentation by dendritic cells (DCs), amplifying CD8+ T-cell activation and strengthening the immune response [14], [15]. The affect of autophagy on tumor-associated macrophages (TAMs) has additionally been investigated. Our analysis revealed that gold nanoparticles can attenuate the M2 polarization of TAMs by inducing lysosomal dysfunction and inhibiting autophagic flux, thereby probably enhancing the efficacy of immunotherapies [16]. The modulation of the autophagy pathway represents a strategic strategy in most cancers therapy, with medicine akin to CQ being employed to enhance the anticancer results of chemotherapy [17]. Moreover, SAL interferes with the autophagy-lysosomal pathway, intensifies DNA harm, and promotes apoptosis [18]. These findings counsel that SAL might be repurposed as an autophagy inhibitor, suggesting a novel therapeutic technique to induce ICD and recondition the immunosuppressive TME within the battle in opposition to most cancers.
Nevertheless, the poor aqueous solubility of SAL impacts its bioavailability and pharmacokinetics, limiting its scientific software [19]. Nanotechnology, significantly using liposomes, has emerged as an answer to reinforce drug solubility, stability, and concentrating on whereas minimizing unintended effects [20], [21]. Liposomal drug supply methods have been efficiently translated into scientific use, with merchandise akin to Doxil® receiving regulatory approval [22], [23]. Nevertheless, issues stay about liposomes probably inflicting immune responses and nontarget tissue accumulation [24]. TNV supply a focused therapeutic benefit due to their tumor-specific biomolecule content material [25]. TNV also can stimulate DC maturation and induce antitumor immune responses [26]. Nevertheless, the immunosuppressive TME and low immunogenicity of some tumors might restrict the therapeutic impact of TNV [27]. Our analysis has developed a novel fusion of TNV and liposomes, leveraging the concentrating on properties of TNV and the drug-encapsulation capabilities of liposomes to beat particular person limitations and modulate the TME successfully [28]. This dual-mechanism technique goals to elicit a potent antitumor response, representing a extra efficacious strategy to most cancers therapy.
The current investigation introduces an progressive nanoformulation, the SAL-loaded liposome hybrid nanovesicle system (SAL@LINV), which represents a big development in drug supply expertise. This technique was synthesized by merging drug-laden liposomes with tumor necrosis virus (TNV) by way of a steady extrusion method. SAL@LINV capitalizes on the excessive drug-loading capability and enhanced stability of liposomes whereas additionally leveraging TNV’s intrinsic means to focus on and activate the TME. Our research meticulously examined the influence of SAL@LINV on autophagy, a pivotal mobile course of within the TME. These outcomes point out that SAL@LINV has the potential to control the TME and bolster the anticancer immune response. The exact concentrating on mechanism of SAL@LINV is theorized to contain disruption of the TME, modulation of mobile autophagy, induction of ICD in tumors, enhancement of antigen presentation by DCs, and reprogramming of macrophage polarization towards the M1 phenotype, as depicted in Scheme 1. This “three-in-one” technique successfully addresses the advanced challenges posed by the TME. By modulating autophagy by nanoparticle-based supply, SAL@LINV strengthens the capability of the immune system to fight tumors. These findings underscore the potential of SAL@LINV as a promising candidate for enhancing immunotherapeutic methods.
