**1. Introduction**

The first line of response of mammalians against pathogenic invasion is innate immunity [1]. It consists of different molecules produced and released by various cell types belonging to the organs, immune or other systems [1]. Among these molecules, we find proteins with direct antimicrobial activity or those which activate the complement proteins [1]. Furthermore, small peptides play an essential role thanks to the presence of specific cationic sequences that interact with the membrane of the pathogens [1,2]. These molecules are called host defense peptides and are more widely known as antimicrobial peptides (AMPs) [2]. They can not only act through different antimicrobial mechanisms of action but [1,2] also with different intensities against an extensive collection of pathogens [1–4]. However, in light of the potential human clinical application, they can be classified as endogenous AMPs produced by the human organism, such as Defensins, Cathelicidins and Dermcidins [3,4]. On the other hand, exogenous AMPs are produced by microorganisms themselves, plants, insects, amphibians and fishes or mammals but

**Citation:** Scavello, F.; Amiche, M.; Ghia, J.-E. Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors. *Pharmaceutics* **2022**, *14*, 2014. https://doi.org/ 10.3390/pharmaceutics14102014

Academic Editor: Rakesh Tiwari

Received: 24 August 2022 Accepted: 20 September 2022 Published: 22 September 2022

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not identified in humans, such as Thionins, Piscidins, Cecropins and Dermaseptins [5–9]. However, increasing data show that these AMPs are multifunctional peptides (MF-AMPs) with different roles in cardiovascular, nervous and renal systems [10–12]. They are also reported as chemokines, vaccine adjuvants, regulators of the innate defense, immunomodulators and anticancer agents [13,14]. All these properties of MF-AMPs confer to these molecules a broad spectrum of potential applications in the biomedical field. The 20th century will be remembered as the time when antibiotic resistance became a world health problem [15]. Different studies reported this issue and recommended limiting the use of antibiotics to contain the evolution of resistant bacteria [15,16]. However, to the present day, the problem is not solved. The World Health Assembly recognized antibiotic resistance as an alarming issue in human medicine and a leading cause of worldwide death [15,17]. In this context, the MF-AMPs appear to be a possible alternative to antibiotics and have acquired an increasingly clinical interest [18]. At the same time, prevention of nosocomial infection and inflammatory activation of the intervention site after the implantation of medical devices is a significant hospital challenge [19]. Additionally, in this case, MF-AMPs are promising, and several studies reported their functionalization of biomaterials, conferring antimicrobial and anti-inflammatory properties [20]. Finally, some of these agents can modulate systemic and tissue inflammation and immune cell activation [21], supporting future clinical applications as immunomodulators. At the same time, several studies showed the activities of these agents against different models of cancer cells, demonstrating a profile of MF-AMPs with potential clinical application also in cancer therapy [14]. Therefore, the principal aim of this review is to report AMPs as multifunctional agents for future clinical applications. More specifically, we will focus on endogenous Chromogranin A-derived peptides for immunomodulation and Dermaseptins as exogenous agents for cancer therapy.
