Stimulators of immunogenic cell death for cancer therapy: focusing on natural compounds

Abstract

A growing body of evidence indicates that the anticancer effect of the immune system can be activated by the immunogenic modulation of dying cancer cells. Cancer cell death, as a result of the activation of an immunomodulatory response, is called immunogenic cell death (ICD). This regulated cell death occurs because of increased immunogenicity of cancer cells undergoing ICD. ICD plays a crucial role in stimulating immune system activity in cancer therapy. ICD can therefore be an innovative route to improve anticancer immune responses associated with releasing damage-associated molecular patterns (DAMPs). Several conventional and chemotherapeutics, as well as preclinically investigated compounds from natural sources, possess immunostimulatory properties by ICD induction. Natural compounds have gained much interest in cancer therapy owing to their low toxicity, low cost, and inhibiting cancer cells by interfering with different mechanisms, which are critical in cancer progression. Therefore, identifying natural compounds with ICD-inducing potency presents agents with promising potential in cancer immunotherapy. Naturally derived compounds are believed to act as immunoadjuvants because they elicit cancer stress responses and DAMPs. Acute exposure to DAMP molecules can activate antigen-presenting cells (APCs), such as dendritic cells (DCs), which leads to downstream events by cytotoxic T lymphocytes (CTLs) and natural killer cells (NKs). Natural compounds as inducers of ICD may be an interesting approach to ICD induction; however, parameters that determine whether a compound can be used as an ICD inducer should be elucidated. Here, we aimed to discuss the impact of multiple ICD inducers, mainly focusing on natural agents, including plant-derived, marine molecules, and bacterial-based compounds, on the release of DAMP molecules and the activation of the corresponding signaling cascades triggering immune responses. In addition, the potential of synthetic agents for triggering ICD is also discussed.

Dual Role of Alchemilla vulgaris L. Extract in Breast Cancer Regression: Reestablishment of Effective Immune Response

“…The results presented in this study show that administration of A. vulgaris extract might raise the immunogenicity of a tumor, making the antitumor immune response more efficient. There is growing evidence that naturally occurring compounds are potent inducers of immunogenic cell death, triggering the release of danger-associated molecules, and therefore serve as immunoadjuvants [ 16 ]. This cascade of events amplifies the two branches of the immune response, innate and adaptive.…”

“…Apart from well-known tumor immune evasion strategies, the TME architecture and extracellular matrix construction enables recruitment of tumor suppressors such as MDSCs and Tregs that orchestrate the establishment of local immunosuppression [ 13 , 14 , 15 ]. Considering the tumor tissue as a never-healing wound, control points of immune response regulation support the entry of effector cells into the exhaustion state [ 16 ]. Therefore, cancer therapy should not only aim to destroy tumor cells but also trigger the flow of events leading to refreshed antitumor immune response.…”

“…When it comes to the complex mixture of compounds in the organic extract, two types of interactions and the crosstalk between them may be crucial—a direct effect on tumor cells and the potential to affect the phenotype and function of immune cells. The immunogenic death of tumor cells induced by various plant polyphenols leads to the release of danger signals and the subsequent refreshment of the antitumor immune response through enhanced potential of antigen-presenting dendritic cells and effector T-cell responses [ 16 ]. Finally, natural products can disrupt the inhibitory signals responsible for creating an immunosuppressive environment in tumors and refresh T-cell effector performance.…”

Challenges of Regulated Cell Death: Implications for Therapy Resistance in Cancer

“…Therapeutic engagement of ICD in cancer may lead to more effective responses by eliciting antitumor immunity. Several classic ICD inducers, including anthracyclines, cardiac glycosides, oxaliplatin, and cyclophosphamide have been extensively used in controlled studies for the inhibition of tumor growth [168]. Interestingly, photodynamic therapy with hypericin has been shown to induce oxidative ER stress, leading to the early exposure of CRT on the cell surface, active secretion of ATP, and passive release of HSP70 and HSP90 during late apoptosis.…”