The gastrointestinal helminths of public health concern usually use humans as natural, final hosts, while the natural life cycle of anisakids includes several aquatic organisms, and humans are accidental hosts not accounted for in the natural evolution processes, such as co-evolution and/or co-adaptation, that have occurred over time between hosts and parasites ^[22][35]. Despite that, only one L3 is sufficient to cause clinical outcomes in humans. A few hours after ingestion, the L3 reaches the gastrointestinal tract. Through a combination of mechanical tissue disruption and release of secrete/excrete (E/S) factors, such as soluble, potent proteolytic enzymes able to degrade the extracellular matrix ^[23][36], together with the extracellular vesicles, including exosomes, the L3 starts to invade the mucosa and submucosa of the gastrointestinal tract. Audicana et al. ^[24][37] described this mechanism in a time-dependent manner, accounting for a progressive process that leads to ulcerous, erosive and granulomatous lesions ^[24][25][37,38]. Helminths, such as Anisakis, are macro pathogens, a condition that prevents them from being quickly captured by phagocytic cells. Therefore, immunomodulating messengers released by immune cells and the parasite itself play a pivotal role in host–parasite interactions, contributing to the onset of an inflammatory microenvironment able to induce a specific Th2 response ^[26][27][39,40]. The epithelial barrier, macrophages (MØ) and dendritic cells (DCs) represent the first line of the human innate immune response. A further pivotal element of the innate immune response is the receptors and, among them, toll-like receptors (TLRs) are the most investigated in several helminthic infections ^[28][41]. In particular, DCs identify Schistosoma mansoni lipid antigens containing phosphatidyl serine through TLR2, while glycoprotein ES-62 of filarial nematodes is recognized through TLR4 ^[29][42]. Despite their relevance, information about TLRs in anisakiasis is still poor and not clear. Usually, the activation of TLRs leads to downstream intracellular signaling. The MAPK pathway is one of the main signaling cascades associated with TLRs stimulation, and it is composed of the extracellular, signal-related kinases 1 and 2 (ERK 1/2), p38 MAPK and c-jun NH2-terminal kinase (JNK). ERK 1/2 usually induces Th2 activation during infections due to extracellular pathogens ^[30][43], while P38 and JNK are mostly involved in the Th1 responses commonly reported for intracellular pathogens ^[31][44]. Once activated, these molecules induce gene expression, DC maturation and cytokine production via the phosphorylation of transcription factors, such as activating protein 1 (AP-1) and nuclear factor-κB (NF-κB) ^[32][45]. The cytokine and chemokine milieu derived from the innate immune cells activation results in the release of specific, pro-inflammatory products, such as thymic stromal lymphopoietin (TSLP), eotaxin and interleukins, such as IL-25, IL-4, IL-5, IL-13, IL-9 and IL-33 ^[27][40], that contribute to DC activation and type 2 response initiation. It was demonstrated that mice deficient in IL-25 are susceptible to infection with the rodent whipworm Trichuris muris, and mice with a dysregulation in TSLP production are unable to induce Th2-driven worm expulsion ^[33][46]. The tissue damage and the release of inflammatory products allow the recruitment of competent cells, such as neutrophils, eosinophils and basophils, among several others, in the site of damage. Actually, one of the main signatures of local lesions produced by Anisakis larvae is the presence of an appreciable eosinophilic infiltration in the tissues surrounding the parasite ^[24][37]. At this point, mature DCs migrate to lymph nodes, priming T naïve cells and giving arise to a Th2 clonal proliferation. The triggering of the Th2 response induced by intestinal nematodes leads to a stereotyped signal cascade of effector mechanisms, including immunoglobulin E isotype-switched B-cell responses, increased permeability, epithelial cell turnover, smooth muscle contractility, mucus production, eosinophilia and mastocytosis, with consequent parasite expulsion ^[34][47]. To avoid this, helminths have devised different strategies to manipulate the host immune system. The alarmin release inhibitor E/S product HpARI released by murine intestinal nematode Heligmosomoides polygyrus suppresses the IL-33 ablating Th2 response ^[35][36][48,49]. Again, asu-miR-5361-5p, a miRNA observed in adult pig roundworm Ascaris suum exosome content, downregulates CD80, a receptor involved in the induction of T-cell proliferation and cytokine production ^[37][50]. The suppression of the host immune response and tolerance can lead to a parasite persistence and chronic inflammation. During chronic anisakiasis, the persistent stimulus of the L3 amplifies the inflammatory state and continuously attracts eosinophils, as well as neutrophils, lymphocytes, monocytes and fibroblasts, recruited to deposit connective tissue to form a granuloma ^[25][38]. The main role of granuloma is to protect the host from pathogens and/or persistent irritants and, after larval death, Anisakis remains are broken down, in time, becoming unrecognizable. This phenomenon contributes to complication of the diagnosis; thus, Anisakis-induced granulomas have been misdiagnosed for tumors in the past but gradually disappear in infected patients, leading to the term “vanishing tumors”.