The development of cancer involves the acquisition of hallmark capabilities and enabling characteristics which are essential for the formation of malignant tumors (Hanahan, 2022). The neoplastic micro-environment which is crucial for the development, expansion, and metastasis of malignancies also contains potential therapeutic targets (Xiao and Yu, 2021). Finding efficient treatment methods are crucial since it is predicted that in the next 20 years, the number of newly diagnosed cancers will rise by approximately fifty percent, globally (Mao et al., 2022).

The common approaches for tackling human cancers are chemotherapy, surgery, radiotherapy and immunotherapy, among which chemotherapy and radiotherapy remain the most widely used. However, these therapies have a wide variety of undesirable side effects, including systemic toxicity, psychiatric issues, as well as the development of highly drug-resistant tumor cells. While chemotherapeutics continue to be widely used, they are not selective towards cancer cells, because of which a significant percentage of healthy cells are also annihilated during the treatment (Liu et al., 2015). Indeed, the most difficult aspect of treating cancer is to eliminate a tumor while sparing healthy cells. However, there have been significant advancements in overcoming the constraints of traditional cancer therapy in recent years (Debela et al., 2021) with folk medicine eliciting much interest in the development of modern medicines which have significantly influenced cancer therapeutics (Yuan et al., 2016). Nature-derived nutraceuticals are garnering great interest due to their structural flexibility which enables them to interfere with crucial signaling components of neoplastic cells, effectively hindering cancer hallmarks (Newman and Cragg, 2020). There have also been concerted efforts towards the discovery of novel peptides from natural sources in order to combat the side effects of chemotherapy and radiotherapy (Dutta et al., 2019). Peptides isolated from natural sources have several benefits over small molecules and biological agents, such as reduced production costs, better tumor tissue penetration, lower immunogenicity and toxicity, binding specificity to the targets, and more adaptable sequences (Abbas et al., 2019; Zhang Y. et al., 2023). Another area of interest has been the discovery of specific nature-derived nano-delivery systems to combat drug resistance as well as adverse side effects (Patra et al., 2018).

Arthropoda is the largest phylum in the animal kingdom, comprising approximately 80% of all living organisms. Class insecta under this phylum possesses vast diversity. Insects serve as sources of medicinal products, therapeutics, and recycling of biological material. Entomophagy, the consumption of edible insects due to their high nutritional value, taste, or associated religious beliefs, has been practiced in many regions of the world since ancient times, particularly in nations like China, Thailand, India, Africa, Latin America, and Mexico (Raheem et al., 2019). Insect extracts have been used as components of folk medicines for various diseases like flu, colds, infections, flatulence, and spasms (Ratcliffe et al., 2011). Insects are also rich sources of proteins, vitamins, chitins, essential amino acids, polyunsaturated fatty acids, and minerals (Oonincx et al., 2010; Boland et al., 2013).

Developing innovative and environment-friendly approaches for new food and drug sources through the effective use of natural resources is amassing worldwide interest (Newman and Cragg, 2020). Insects generate food items and by-products that have a variety of nutritional and practical values, as well as disease-ameliorating properties (Quah et al., 2023). Thus, in recent years, interest in consumption of insects as food has increased due to their established health benefits. There is also increasing interest in the use of insect derived products such as silk, and the silk proteins fibroin and sericin as biomaterial for the formulation of novel nanoparticles and drug delivery systems, owing to their biocompatibility, biodegradability, non-toxicity and low immunogenicity. The silk-based nanoparticles are loaded with chemotherapeutics, natural drugs like curcumin, peptides and proteins, and have also been used for the delivery of nucleic-acid based therapeutics like small interfering RNA (siRNA), micro RNA (miRNA) and antisense oligodeoxynucelotides (ASO) (Florczak et al., 2020).

This review focuses on the role of natural products derived from insects as anticancer therapeutics, and also summarizes their more recent role in the formulation of nanoparticles and nano-cargoes for effective cancer therapy.

Over 2,100 kinds of insects have been categorized as edible, and it is believed that over 2.5 billion people, primarily in Asia, Africa and Latin America ingest insects in various ways (Zhang E. et al., 2023). The indigenous people of several nations such as South America, India, Mexico, Korea, China and Nigeria have a long history of treating ailments using insects (Devi et al., 2023). Lepidoptera are the most commonly used therapeutic insects in Japan, Hemiptera and Orthoptera in India, and Coleoptera, Hymenoptera, Orthoptera, and Homoptera in Brazil (Costa-Neto, 2005). Traditional Chinese Medicine (TCM) has utilized silkworms and flies for healing infected wounds (Sherman et al., 2000; Costa-Neto, 2005) for at least three thousand years (Zimian et al., 1997). Approximately 77 species of insects are also reported to be used in TCM for anti-tumor effects. These include cantharis Mylabris spp., caterpillar, bees, wasps, silkworm Bombyx mori, house fly Musca domestica, ants and grubs (Feng et al., 2009). In certain regions of Brazil, adding ground ants to coffee or juice mixed with sugar is used to alleviate eye ailments (Costa-Neto, 2002). Apitherapy involves employing bee products for therapeutic purposes, which is the most common traditional therapy used by indigenous people for the treatment of cold, cough, stomach pain and fever. Numerous antibacterial peptides and proteins, including cecropins, defensins and lysozymes, are produced by butterflies (Siddiqui et al., 2023). In sub-Saharan Africa, numerous insects are consumed as food supplements because of their high protein and essential amino acid content. They are also used to treat flu, asthma, bronchitis, whooping cough, tonsillitis, sinusitis, and hoarseness (Jideani and Netshiheni, 2017). Insect derived products are frequently used in the Indian traditional medicine system of Ayurveda for treatment of various diseases including anemia, asthma, rheumatism, malaria and ulcer (Wilsanand et al., 2007).

Anti-cancer therapeutics can exert their effects through various mechanisms such as by influencing the genes that regulate the cell cycle, by inducing apoptosis, or by inhibiting proliferation. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway is an important signaling pathway controlling the proliferation and survival of cells. Malignant neoplasia such as breast, lung, ovarian, and prostate tumors exhibit aberrant activation of this pathway. Increased activity of the pathway is frequently linked to the development of tumors and resistance to cancer treatments. A potential therapeutic agent can thus produce anti-cancer effects by modulating the intermediates of the PI3K-AKT pathway (Yang et al., 2019; Liu R. et al., 2020). Cecropin inhibits Bcl2 through its BH3 like motif and also upregulates pro-apoptotic proteins (Jin et al., 2010; Maaroufi et al., 2021). As forkhead box O proteins (FOXOs) build up in the nucleus, they can bind to different transcriptional cofactors and control the expression of genes involved in the growth of cells, survival, proliferation, cell division, apoptosis and metabolism. The primary route controlling the transcriptional activity of FOXOs is the PI3K/Akt pathway (Burgering and Medema, 2003). Solenopsin is reported to exert anti-cancer effects by inhibiting Akt phosphorylation and activation of its downstream protein, FOXO1 (Arbiser et al., 2007; Uko et al., 2019). Sericin induces apoptosis via caspase dependent pathway, and enhances expression of the pro-apoptotic proteins Bax, Bim, Puma and Noxa by inhibiting the anti-apoptotic protein, Bcl2 (Kaewkorn et al., 2012; Kumar et al., 2019). It also induces p53-dependent apoptosis in cancer cells (Jolly Devi et al., 2023).

The anticancer mechanisms of insect-derived active components sericin, cecropin, solenopsin and melittin have been depicted in Figure 1.

The cGAS-STING pathway regulates several pathological processes brought on by the immunological response to the ectopic localization of self-DNA, including cytosolic mitochondrial DNA, in addition to protecting cells against a variety of DNA containing pathogens. Besides its well established antimicrobial properties, melittin creates pores in the cell membrane and the mitochondrial membrane, and may lead to exposure of mitochondrial DNA in the cytoplasm of cancer cells (Díaz-Achirica et al., 1994; Wang et al., 2022). It also causes morphological changes in the cell membrane and DNA damage in leukocytes even at non-cytotoxic doses (Guha et al., 2021). The presence of cytosolic DNA and DNA damage are detected by cyclic GMP-AMP synthase (cGAS) which activates the stimulator of interferon genes (STING), leading to cGAS-STING mediated cell death, induction of type-I interferons and cytokine production, ultimately inducing apoptosis and anti-tumor immune activation. The generation of type I interferons by the stimulation of the cGAS-STING pathway has the potential to significantly enhance anti-tumor immunity (Gan et al., 2022). It is reported that MnO2-melittin nanoparticles activate the cGAS STING pathway to produce anticancer activity (Tang et al., 2022). ER stress leads to release of Ca²⁺ ions to the cytosol which trigger mitochondrial membrane permeability and pore formation, resulting in leakage of mitochondrial DNA to the cytosol (Smith, 2021). Melittin induces ER stress and release of Ca²⁺ through IP3, thus inducing ER mediated apoptosis (Luo et al., 2023). The anticancer mechanisms of melittin and cecropin through the cGAS STING pathway have been illustrated in Figure 2.

Inflammation is intimately linked to all phases of the onset and spread of malignancy in the majority of cancers, as well as to the effectiveness of anti-cancer treatments (Bader et al., 2020; Arner and Rathmell, 2023). The immune system is assisted by immunotherapy in identifying and eliminating cancer cells. By combining vaccinations with immunostimulatory cytokines or by inhibiting the mechanisms that cancer cells employ to dampen the response, immunotherapy seeks to increase the immune system’s ability to fight cancer (Markman and Shiao, 2015). Immunomodulation for the treatment of cancer involves two factors: (1) enhancing the immune system’s capacity to combat cancer by turning on anti-cancer immune cells (2) Blocking pro-cancer immune cells or causing them to polarize towards anti-tumor types by focusing on essential signaling pathways which can slow the development of cancer (Locy et al., 2018).

Various studies have reported that insect derived bioactive compounds and insect extracts possess immunomodulatory activity. A coleopteran insect Mimela sp. belonging to Scarabaedae family is an entomophagous bug mostly consumed in Korea, Northern Thailand, and the state of Arunachal Pradesh in India. Studies reported that it has antioxidant, immunomodulatory and anti-tumorigenic activities. Mimela sp. extract elevated the leucocyte count in cyclophosphamide treated mice. It also increased TNF-α and IL-6 in immunosuppressed mice (Tukshipa and Chakravorty, 2022). Eupolyphaga sinensis Walker is a wingless edible cockroach belonging to order Blattaria and the family Polyphagidae. In vivo studies reported that E. sinensis extract enhances immunity in mice, improves lymphocyte production and also stimulates T-cell mediated delayed type hypersensitivity (Tang et al., 2010). Lectins isolated from the edible insect pupae of Musca domestica belonging to family Muscidae show immunomodulatory and anti-tumor effects. Three galactose specific lectins (40kDa, 55kDa and 80 kDa) show potent immunomodulatory activity on murine peritoneal macrophages, enhancing the phagocytic activity of macrophages via NF-kB pathway and increasing the expression of TNF-α, IL-6 and INF-γ (Cao et al., 2012). In vivo studies on mice model revealed that freeze dried Tenebrio molitor larvae enhance the phagocytic activity of macrophages in mice. It produces immunomodulatory effects by intensifying the non-specific, cellular and antibody mediated immune responses (Tang and Dai, 2016).

In vivo studies on mice injected with sarcoma S180 cells revealed that a peptide fraction extracted from Musca domestica larvae showed immunomodulatory activity by encouraging the growth of splenocytes, NK and CTL activity, and boosting serum levels of IgG, IgG2a, and IgG2b antibodies that are specific for the antigen in S180 sarcoma cells in mice. Additionally, the peptide fraction elevated the mRNA expression of INF-γ, and promoted Th1 response by elevating the expression of transcription factor T-bet and STAT-4 in sarcoma S180 cell bearing mice (Sun et al., 2014). Bee products are well known for their antioxidant, anti-inflammatory and anti-tumor effects. Recent in vivo and in vitro studies reported the immunomodulatory effects of bee pupae peptide, BPP-22. It enhanced the production of antibodies IgA, IgE, IgM, IL-2, INF- γ and elevated the phagocytic activity of macrophages in an immunosuppressied mouse model. It is suggested that BPP-22 exerts its immunomodulatory effects by elevating the phosphorylation of ERK and p38 and modulating the MAPK signaling pathway (Chen et al., 2022).

Mellitin has been reported to have a range of immune-modulating effects in several studies. Melittin alone or in conjugation with other anticancer peptides enhanced the secretion of IL-2 and TNF-α, elevated the proliferation of splenocytes and cytotoxicity of NK cells, enhanced Th1 specific INF- γ production, and increased the activity of macrophages. Melittin is also used as a tumor vaccine in vitro in conjugation with other components to induce the immune reaction and enhance the activity of dendritic cells to kill melanoma cells. Injectable hybrid vaccine hydrogel was prepared by conjugation of melittin, RADA32 (cell assembling peptide), CpG (immune adjuvant) and tumor lysate. This hybrid vaccine showed anticancer activity in vivo by elevating cytotoxic T lymphocytes (CTLs) and activating dendritic cells in draining lymph nodes in melanoma B16-F10 xenograft mice (Yang K. et al., 2023).

The immunomodulatory activity of different insect peptides against cancer is depicted in Figure 3. Dendritic cells (DCs) undergo functional morphological modification and activate T helper cells (T CD4⁺) and T cytotoxic cells (T CD8⁺). T helper cells release cytokines and other mediators that control other immune cells. These cytokines activate and polarise monocytes and macrophages as well as control the antibodies produced by B cells. As a result, Th cells are essential to the anti-cancer immune system. On the other hand, the T cytotoxic cells (T CD8⁺) migrate towards the cancer cells and directly destroy them by releasing granzymes and perforins. NK cells also enhance the maturation of T CD8⁺ (Hosseinzade et al., 2019).

Melittin, in combination with tumor vaccine shows immunomodulatory anti-cancer efficacy by enhancing the maturation of DC to T CD4⁺ and T CD8⁺ cells (Yang K. et al., 2023). Other insect peptides show their immunomodulatory activity by enhancing the maturation of DC and NK cells. This in turn activates T CD8⁺ cell and destroy cancer cells (Tang and Dai, 2016). Insect derived lectins show anti-cancer immunomodulatory activity through M1 macrophage mediated phagocytosis (Cao et al., 2012). The capacity of insect peptides to modify the immune response against cancer cells has been shown in several researches (Sun et al., 2014; Chen et al., 2022; Yang K. et al., 2023). It has been seen that, some insect peptide fragments interact with immune cells, including DC, natural killer (NK) cells, and T lymphocytes, among others, and enhance their activity. For instance, it has been demonstrated that certain insect peptides can increase NK cells’ cytotoxic activity, which aids in the elimination of cancer cells. Others have been discovered to support dendritic cell maturation and activation, enhancing antigen presentation and subsequent T cell activation.

The rise of multidrug resistance and the toxicity of standard chemotherapy drugs drives research towards targeted medicine. Efforts directed towards encapsulating and releasing anticancer medicines more effectively, raise the possibility for the nano-biomedical field to produce efficient, therapeutic, nano-sized drug delivery systems (Yao et al., 2020). Nano-oncology imparts more efficient delivery of chemotherapeutics by reducing systemic toxicity and enhancing accumulation directly to the targeted tumor microenvironment (Misra et al., 2010). Nanoparticles derived from natural compounds have been reported to have better safety profiles, revamped stability, biodegradability, and non-immunogenicity in comparison to synthetically derived nanoparticles. They also possess functional groups that can be easily modified in order to improve effcicacy. Furthermore, their high biocompatibility, hydrophilicity and lowered bio-toxicity, make bioactive components good candidates for use as nanoparticles or nano-cargo to deliver chemotherapeutics (Ion et al., 2022). A crucial aspect of nano-cargo for delivering therapeutics is their ability to target cancer cells precisely, which boosts therapeutic effectiveness while shielding healthy cells from damage (Cheng et al., 2021). Various by-products from insects have been employed for this purpose.

Silk extracted from the silkworm consists of mainly two proteins viz. sericin and silk fibroin (Kunz et al., 2016). The silk fibroin is an amphipathic beta sheet secondary peptide consisting of one heavy chain (365 kDa) and one light chain (26 kDa) joined together by disulfide bond. The heavy peptide chain is composed of a repetitive motif of 6 amino acids (Gly–Ala–Gly–Ala–Gly–Ser)n flanked by N & C terminal domains. Silk fibroin is a promising biomaterial for biomedical applications due to its distinctive structure, processing adaptability, biological compatibility, variety of biomaterial morphologies, facile sterilization, thermal resilience, surface chemistry for chemical alterations, and water solubility (Zhou et al., 2001; Jastrzebska et al., 2015; Philipp Seib, 2017), and has received formal FDA approval as a biocompatible material (Cao et al., 2017). It has been transformed to nanomaterials drug administration following its modification into films, hydrogels, coatings, capsules, micro- and nanoparticles. Fibroin nanoparticles (FNPs) can encapsulate and deliver a variety of therapeutic compounds, including small and large molecules, proteins, enzymes, vaccines, and genetic materials to target cells (Pham and Tiyaboonchai, 2020). Silk fibroin based nanoparticles are used for drug delivery by intratumoral injections and intravenous injections (Jastrzebska et al., 2015). Silk fibroin microparticles and nanoparticles have been found to be active against inflammation and its associated disorders such as arthritis and cancer (Dutta et al., 2019). Silk fibroin nanoparticles (SFNPs) loaded with chemotherapeutic drugs such as doxorubicin, cisplatin, paclitaxel, methotrexate and 5-Flurouracil proved effective at delivering the drugs and exerting anti-cancer effects in vitro. SFNPs loaded with paclitaxel alone or gemcitabine conjugated with SP5-52 peptide also showed anti-cancer efficacy in vivo in a mice model of gastric cancer and Lewis lung tumor, respectively. SFNPs loaded with binary drugs such as hydrophilic doxoribucin and hydrophobic paclitaxel were effectively internalized and inhibited the growth of cancer HeLa and HepG2 cells more effectively than when the nanoparticles were loaded with a single drug, indicating the efficiency of these nanoparticles as drug delivery systems for combination therapy. B. mori SFNPs loaded with curcumin were also used to deliver the phytocompound curcumin to different cell lines, resulting in significantly higher uptake and stronger anti-cancer effects in the breast cancer cell lines MCF-7 and MDA-MB-453, hepatocellular carcinoma Hep3B cells and neuroblastoma KELLY cells and HCT116 human colorectal cancer cells, compared to free curcumin. Furthermore, SFNPs loaded with plant-derived anticancer substances produced significant cytotoxic effects in cancer cells while maintaining no cytotoxicity towards healthy cells (Florczak et al., 2020).

Polyethyleneimine-modified SFNPs (PEI-SFNPs) used to co-deliver doxorubicin and survivin siRNA effectively induced apoptosis in the 4T1 mouse tumor cell line and remarkably reduced the growth rate of breast tumor in 4T1 tumor bearing mice by suppressing the survivin gene (Norouzi et al., 2021).

The silk cocoon protein, sericin, is also used in nanobiotechnology for formulating drug delivery systems. It contains hydroxyl group-containing amino acids which enable it to copolymerize with other molecules for the synthesis of novel biodegradable and biocompatible compounds that can be used for drug delivery, in vivo cell imaging, and other biomedical uses (Ahn et al., 2001; Cho et al., 2003; Kumar and Mandal, 2019; Elahi et al., 2021). Sericin based nanostructures can potentially deliver hydrophobic and hydrophilic chemotherapeutic drugs more rapidly into cancer cells, compared with the chemotherapeutic drug alone (Elahi et al., 2021). Sericin coated AgNO₃ nanoparticles showed potent anticancer efficacy against the breast cancer cell lines, MCF-7 and MDA-MB-231, by inducing apoptosis, cell cycle arrest, and cancer cell specific cytotoxicity, while simultaneously reducing the side effects of the nanoparticles (Mumtaz et al., 2023; Kara et al., 2020 reported the use of nanocarrier composed of a blend of albumin and silk sericin for in vivo delivery of miRNA. They reported significant in vivo tumor integration of miR-329 and inhibition of the eukaryotic elongation factor-2 kinase (eEF2K) protein in multiple triple-negative breast cancer (TNBC) models with pronounced anti-tumor efficacy and without any side effects in mice. Albumin-sericin nanoparticles (Alb-Ser NPs) further functionalized by complexing with poly-l-lysine/siRNA and hyaluronic acid were also used for delivery of siRNA targeting casein kinase 2 (CK2), Absent, Small, or Homeotic-Like (ASH2L), and Cyclin D1 (CCND1) genes to the laryngeal cancer Hep-2 cells. The nanoparticles loaded with siRNA silenced the target genes significantly more effectively when compared with naked siRNA, resulting in significant cytotoxicity of the targeted cells (Yalcin et al., 2019).

Sericin is sensitive to pH due to its constituent amino acids with strongly polar side groups, and has been extensively studied for formulating pH-responsive delivery systems (Silva et al., 2022). In one study, folate-conjugated sericin nanoparticles were used for targeted subcellular delivery of doxorubicin to the folate-receptor-rich human oral epithelium carcinoma cell line (KB). Once inside the cells, the acidic environment of the lysosomes that contained the endocytosed nanoparticles prompted the rapid release of doxorubicin, producing significant anti-cancer effects (Huang et al., 2016). In another study, synthetic poly(γ-benzyl-L-glutamate) (PBLG) conjugated sericin micelles loaded with doxorubicin (Sericin-PBLG-DOX) induced significant cytotoxicity in adriamycin resistant MCF-7 ADR cells and HepG2 ADR cells in vitro as well as in vivo in tumor bearing nude mice transplanted with MCF-7 ADR cells and HepG2 ADR cells through enhanced cellular uptake and pH-triggered drug release (Guo W. et al., 2018). A surface charge reversal sericin-based nanocarrier used to co-deliver resveratrol and melatonin to MCF-7 breast cancer cells as combination therapy, also proved to be effective in delivering the drugs effectively and inducing apoptosis of the breast cancer cells in an acidic environment (Aghaz et al., 2023).

AgNO₃ nanoparticles synthesized from the wings of Mang mao insect showed broad spectrum anti-bacterial and anti-fungal activities along with strong antioxidant efficacy (Jakinala et al., 2021). Silver nanoparticles synthesized from the defensive gland extract of Mupli beetle, Luprops tristis Fabricius showed potential anticancer efficacy against DLA (Dalton’s Lymphoma Ascites) cell line (Ajaykumar et al., 2023).

Mealworm insect protein was designed as a nano cargo for the delivery of curcumin to cancer cells by creating spherical biopolymer nano complexes of sizes d = 143–178 nm which are loaded with curcumin due to hydrophobic and non-covalent interaction between curcumin and insect proteins. These nano complexes enhance the release of curcumin efficiently to the cells but show moderate binding efficacy (Okagu et al., 2020). When compared to conventional approaches, the production of nanoparticles utilizing insect by-products is a more economical strategy. Natural substances found in insect byproducts such as wings, exoskeleton, and extracts serve as economical stabilizers or reducing agents during nanoparticle synthesis, lowering the total cost of production (Jakinala et al., 2021). Characteristics of some nanoparticles derived from different active components of edible insects and their modes of transfer to the cancer tissue has been listed in Table 4.

Crucial aspects of the drug development process include identification and characterization of the active ingredients in natural products, and guaranteeing their stability and consistency. Current methods for drug discovery in contemporary medicine prefer single compound-based treatment over crude extracts of natural products. However, given the multifaceted nature of many ailments including cancer, it is not surprising that the search for effective treatments has not been successful when relying solely on single compounds (Thomford et al., 2018).

While natural products contain several bioactive components, the complexity of the molecular combinations from natural sources makes the search for novel therapeutic possibilities challenging, There are also several limitations to the use of natural products derived from insects and other sources in clinical trials. These include: (i) In vitro preclinical research frequently entails prolonged exposure to elevated quantities of a target natural substance. In humans, this kind of exposure is usually not achievable, especially when it comes to oral drugs that may have a restricted bioavailability; (ii) Safety and allergic reactions is a crucial subject for translation of nature-derived products to human subjects; (iii) insects might acquire diseases or contain residues of pesticides and heavy metals from their natural ecosystem which may raise safety issues; (iv) preclinical efficacy does not always translate into human success, and no dietary supplement research has yet received regulatory clearance; (v) the lack of established protocols for evaluating natural products in preclinical and clinical research is another significant barrier (Paller et al., 2016; Thomford et al., 2018).

Changes in the experimental setting, such as assay methods, dosing regimens, and primary extraction processes, can lead to contradictory findings and reduce the comparability of data from many trials. Establishing guidelines for the description, preparation, and evaluation of natural products can improve the reliability of study results and facilitate regulatory approval of clinical trials (Andrade et al., 2016).

Insects have been traditionally consumed as food and used for the preparation of folk medicine by several populations, globally. Due to rapid growth in population and rising food demand, it is imperative that sustainable, nutrient-dense, and environmentally sustainable alternative food sources explored. Entomophagy has the potential to solve difficulties with nutrition, sustainability, and global food security because insects possess high nutritional value and insect farming is economically sustainable, generates a significant amount of edible biomass with far lower land, water, and feed requirements, and also has a low emission of greenhouse gases (Shah et al., 2022).

Insect extract and insect venom are crucial and time-tested components of complementary and alternative medicine, having been applied and improved by physicians over several generations for treating various disorders (Wainwright et al., 2022). There is strong evidence to support the rising use of insect-derived products and crude extracts as a useful component of treatment and a profusion of experimental evidence demonstrating their vast diversity being used to successfully cure various types of ailments and malignancies. Due to their antioxidant and anti-inflammatory activities, insect extracts and their byproducts have the ability to improve cancer treatment in addition to successfully reducing side effects and symptoms (Dutta et al., 2019). Indeed, various studies indicate that insect-derived bioactive components such as cecropin, sericin and mellitin exhibited significant cytotoxicity in cancer cells, while producing no cytotoxicity in normal cells. This selective action could significantly reduce the unwanted side effects associated with chemotherapy, and warrant further investigations into the cellular mechanisms involved. Traditional medical systems from many cultures have long acknowledged the therapeutic benefits of edible insects and the substances they produce. Through the integration of this age-old knowledge with contemporary scientific discoveries, we can open up new avenues for the development of trustworthy anticancer treatments. Both conventional wisdom and bioactive substances obtained from insects have great promise as trustworthy anticancer treatments. By funding research and fusing traditional knowledge with contemporary technology, we can create efficient medications that are accessible, inexpensive, and sustainable on a global scale. To overcome the limitations related to the use of natural products in clinical trials, more focus is required on establishing standardized protocols for the extraction of bioactive compounds and assessment of the efficacy of natural products. It is also crucial to have strict preclinical and clinical evaluation methodologies in place. As these bioactive compounds show higher synergistic anticancer efficacy in conjugation with other nature derived bioactive compounds or in combination with chemotherapeutic agents, more research should focus on combination therapy. For example, cecropin shows higher anticancer effects in combination with curcumin (Mahmoud et al., 2022); and, a hybrid vaccine developed by conjugating mellitin with RADA32 (cell assembling peptide), CpG (immune adjuvant) and tumor lysate shows strong antitumor immunological activity in melanoma B16-F10 xenograft mice (Yang K. et al., 2023). There should also be more focus on the mode of delivery of chemotherapeutic agents and/or natural products to the target tumors or cancer sites in order to reduce systemic toxicity and improve therapeutic efficacy. In this context, nano-cargo delivery systems based on insect-derived bioactive components such as silk fibroin and sericin protein hold great promise and should be extensively explored.

This evidence based review demonstrates the anti-cancer and immunomodulatory efficacy of edible insect derived extracts and/or bioactive compounds. Edible insects are rich in nutrients such as proteins, amino acids, minerals, vitamins and fatty acids. Additionally, edible insects contain a wide range of useful compounds, including bee venom components; silk cocoon and antimicrobial peptides which possess anticancer immunomodulatory activity. Bioactive components derived from insects act as potent nano-cargo to deliver the therapeutics directly to the tumor microenvironment by lowering the systemic side effects of chemotherapeutic drugs.

Focused research would hasten the development of novel, potent insect-derived therapeutics and drug delivery systems against cancer. However, detailed investigations into the toxicological effects, if any, of these bioactive components, as well as their capacity to traverse the blood-brain barrier, their bioavailability, skin permeability, lipophilicity, and pharmacodynamic qualities, are required. It is also imperative to establish guidelines and standardized protocols for the extraction and preparation of natural products derived from insects, as well as for the evaluation of their efficacy in preclinical and clinical studies. These strategies will enable the transition of significant preclinical findings to translational research, so that the therapeutic potential of insect-derived bioactive components may be fully explored.