This distribution reflects both the natural abundance of AMPs in certain organisms and the research focus in the field. Amphibians, particularly frogs, have been extensively studied due to their rich repertoire of bioactive peptides. The significant presence of human-derived AMPs suggests a growing interest in developing endogenous peptides as therapeutics.

The diversity of sources underscores the vast potential for discovering novel anticancer peptides across different kingdoms of life. It also highlights opportunities for exploring less-studied sources, such as marine organisms and extremophiles, which might yield unique peptides with advantageous properties.

Future research could benefit from a more balanced approach, investigating underrepresented sources while continuing to explore the rich diversity of well-established sources like amphibians and insects. Additionally, the development of synthetic and engineered peptides based on natural templates offers promising avenues for optimizing anticancer efficacy and reducing potential side effects.

In conclusion, this dataset demonstrates the wide distribution of anticancer AMPs in nature and emphasizes the importance of biodiversity in drug discovery efforts. It also underscores the potential for developing novel anticancer therapies from both natural and engineered peptide sources.

The sequence information of reported anticancer peptides was shown in Figure 2 . The data presented on antimicrobial peptides with anti-cancer effects provides valuable insights into how specific structural characteristics influence their anticancer activities. The impact of net charge, peptide length, Boman index, and hydrophobicity on the anti-cancer properties of these peptides can be considered as below:

Net Charge: The net charge of peptides plays a crucial role in their anti-cancer activities. Positively charged peptides are generally more effective against cancer cells due to:

However, the optimal length can vary depending on the specific cancer target and mechanism of action. Some longer peptides might offer more complex interactions with cellular targets.

Boman Index: The Boman index, indicating the potential for protein-protein interactions, is relevant for anti-cancer activities:

On the other hand, a Boman index value of 1 or below suggests that the protein possesses a reduced risk of causing side effects and toxicity. The Boman index, with values less than one, can indicate relatively favorable interactions with cancer cells and, at the same time, exhibit lower toxicity by having weaker interactions with normal cells (38).

Hydrophobicity: The hydrophobicity of peptides is critical for their anti-cancer effects.

The prevalence of helical structures in the data suggests that this conformation is particularly important for anti-cancer activities. Helical structures can:

In conclusion, the anti-cancer properties of these peptides are intricately linked to their structural characteristics. The optimal combination of positive net charge, appropriate length, balanced Boman index, and moderate hydrophobicity can lead to peptides with enhanced selectivity and efficacy against cancer cells. Future research focusing on fine-tuning these parameters could lead to the development of more potent and selective anti-cancer peptides, potentially offering new avenues for cancer therapy with reduced side effects compared to traditional chemotherapeutics.

The comprehensive analysis of these antimicrobial peptides reveals that their various characteristics - including length, charge, structure, Boman index, and hydrophobicity - are all well-suited for their anti-cancer activities. The peptide lengths observed are generally optimal for penetrating tumor tissues and cancer cells, while maintaining selectivity. Their net charges, predominantly positive, facilitate strong interactions with cancer cell membranes. The prevalence of helical structures enhances their ability to disrupt cancer cell membranes effectively. The Boman indices of these peptides suggest a good balance between membrane interaction and potential intracellular activities, which is crucial for diverse anti-cancer mechanisms. Additionally, their hydrophobicity levels appear to be in a range that allows for effective membrane penetration without excessive toxicity to normal cells. Collectively, these characteristics contribute to the peptides’ ability to target and eliminate cancer cells through various mechanisms, including membrane disruption, intracellular targeting, and potential signaling pathway interference. The combination of these properties makes these antimicrobial peptides particularly promising candidates for anti-cancer therapies, offering a multi-faceted approach to combating cancer cells while potentially minimizing harm to normal tissues (37, 39–41).

AMPs exhibit direct cytotoxicity towards cancer cells through several mechanisms, primarily involving interactions with the cell membrane and subsequent induction of apoptosis. The membrane-disrupting activity of AMPs is a key factor in their anticancer effects. AMPs can bind to and insert into the lipid bilayer of cancer cell membranes, leading to membrane destabilization and eventual rupture. This disruption results in the leakage of intracellular contents and cell death. The cationic nature of many AMPs allows them to interact preferentially with the negatively charged phospholipids found in higher concentrations on the surface of cancer cells, enhancing their selectivity and efficacy. In addition to membrane disruption, AMPs can induce apoptosis in cancer cells. This process involves the activation of caspase pathways and the release of pro-apoptotic factors. Some AMPs can trigger the formation of membrane pores, leading to the influx of calcium ions and activation of calpain proteases, which in turn activate caspases and initiate apoptosis. Other AMPs may directly interact with intracellular targets, such as mitochondria, leading to the release of cytochrome c and the activation of the intrinsic apoptotic pathway. The specific structural features of AMPs play a crucial role in their cytotoxic activity. For instance, the amphipathic nature of many AMPs, characterized by a combination of hydrophobic and hydrophilic regions, allows them to interact effectively with the lipid bilayer. The length, charge distribution, and secondary structure of AMPs also influence their ability to disrupt membranes and induce apoptosis. Alpha-helical AMPs, for example, are particularly effective at penetrating and disrupting membranes due to their ability to adopt a helical conformation in the lipid environment (42–45).

AMPs can stimulate the immune system to recognize and eliminate cancer cells, making them valuable agents in cancer immunotherapy. By modulating the immune response, AMPs can enhance the body’s natural defenses against cancer. One mechanism involves the activation of pattern recognition receptors (PRRs) on immune cells, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). These receptors recognize AMPs and trigger signaling pathways that lead to the production of pro-inflammatory cytokines and the activation of immune cells. AMPs can also modulate the function of various immune cells, including dendritic cells, macrophages, and T cells. For example, AMPs can enhance the maturation and antigen-presenting capabilities of dendritic cells, leading to increased activation of T cells and improved immune surveillance of cancer cells. Additionally, AMPs can stimulate the production of cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which have potent antitumor effects. The ability of AMPs to modulate immune cell function and cytokine production makes them valuable tools in enhancing the immune response against cancer. By promoting a more robust and effective immune reaction, AMPs can help eliminate cancer cells and prevent tumor recurrence (32, 46, 47).

The tumor microenvironment plays a critical role in cancer progression, including processes such as angiogenesis, metastasis, and interactions with stromal cells. AMPs can impact the tumor microenvironment in several ways, disrupting these processes and enhancing therapeutic efficacy. One significant effect of AMPs on the tumor microenvironment is their ability to inhibit angiogenesis, the formation of new blood vessels that supply nutrients and oxygen to the tumor. AMPs can target endothelial cells lining blood vessels, disrupting their function and reducing vascular supply to the tumor. This vascular disruption can lead to tumor hypoxia and necrosis, impairing tumor growth and survival. AMPs can also influence metastasis, the spread of cancer cells to distant organs. By disrupting the interactions between cancer cells and the extracellular matrix, AMPs can inhibit the migration and invasion of cancer cells. Additionally, AMPs can target cancer-associated fibroblasts and other stromal cells, reducing their supportive functions and limiting tumor growth. Furthermore, AMPs can modulate the immune cells within the tumor microenvironment, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which often suppress the immune response and promote tumor growth. By reducing the activity of these suppressive cells, AMPs can enhance the antitumor immune response and improve the efficacy of other therapeutic modalities (42, 44, 48).

In summary, the mechanisms of action of AMPs in cancer involve direct cytotoxicity, modulation of the immune response, and targeting of the tumor microenvironment. These multifaceted effects make AMPs promising agents in the development of novel anticancer therapies, offering potential for more effective and targeted treatment strategies.

Preclinical studies in animal models have provided substantial evidence supporting the efficacy of AMPs against various types of cancer. These studies have investigated the effects of AMPs on a wide range of cancers, including solid tumors and hematologic malignancies, and have explored different treatment regimens and delivery strategies.

Solid Tumors: AMPs have demonstrated significant antitumor activity against various solid tumors in preclinical models. LL-37 has shown efficacy against breast cancer in mice, reducing tumor growth and metastasis (76). Another study investigated the effects of magainin II on colon cancer in a rat model, reporting significant tumor regression and improved survival (77). Lactoferricin B has also exhibited potent antitumor activity against melanoma in mice, inhibiting tumor growth and angiogenesis (78). Furthermore, Protegrin PG-1 has demonstrated efficacy against prostate cancer in a mouse model, reducing tumor volume and improving survival (54).

Hematologic Malignancies: AMPs have also shown promise in the treatment of hematologic malignancies in preclinical studies. The LTX-315 has demonstrated potent antileukemic activity in vitro and in vivo, inducing apoptosis in leukemia cells and reducing tumor burden in mouse models (79). Another study investigated the effects of PFR-1 on lymphoma in mice, reporting significant tumor regression and improved survival (80). Additionally, Cyclic AMP has shown efficacy against multiple myeloma in a mouse model, reducing tumor growth and enhancing the effects of conventional chemotherapy (81).

Treatment Regimens and Outcomes: Preclinical studies have explored various treatment regimens and delivery strategies for AMPs in cancer therapy. Single-agent therapy with AMPs has demonstrated significant antitumor activity in several studies (82–85). However, combination therapy approaches have also shown promise. Targeted delivery strategies have also been explored to enhance the efficacy and specificity of AMPs in cancer treatment (86, 87). One study investigated the use of a tumor-targeting peptide conjugated to the AMP cecropin A, demonstrating improved tumor localization and antitumor activity in a mouse model of breast cancer (86). Another study utilized a nanoparticle delivery system to target the AMP melittin to lung cancer cells, resulting in enhanced tumor regression and reduced systemic toxicity in mice (55).

The therapeutic outcomes observed in preclinical studies have been promising, with AMPs demonstrating significant antitumor effects across various cancer types. Tumor regression, metastasis inhibition, and improved survival have been consistently reported in animal models treated with AMPs (76, 77, 81). These findings highlight the potential of AMPs as novel therapeutic agents for cancer treatment and provide a strong foundation for further clinical development.

In conclusion, preclinical studies in animal models have provided compelling evidence supporting the efficacy of AMPs in cancer treatment. These studies have demonstrated the antitumor activity of AMPs against a wide range of solid tumors and hematologic malignancies, explored various treatment regimens and delivery strategies, and reported promising therapeutic outcomes. However, further research is needed to optimize AMP-based therapies, elucidate their mechanisms of action, and address potential challenges in translating these findings to human clinical trials.

The promising preclinical results have led to the initiation of clinical trials in humans to evaluate the safety and efficacy of AMPs for cancer therapy. Several clinical trials are currently ongoing, investigating the use of AMPs for various cancer types. These trials span different phases, each with specific objectives and patient populations (82, 88, 89). Clinical trials are targeting a range of patient populations, including those with advanced cancers who have exhausted conventional therapies, such as in the LTX-315 trial focusing on patients with metastatic solid tumors. AMPs are also being explored as potential treatments for patients with drug-resistant cancers. Additionally, some trials are exploring the use of AMPs as adjuvant therapies in early-stage cancers, such as the bovine lactoferrin trial in head and neck cancer patients aiming to prevent recurrence in those who have undergone primary treatment Preliminary results from early-phase clinical trials are encouraging. In the Phase I trial of LTX-315, 50% of evaluable patients showed stable disease, and one patient metastatic soft tissue sarcoma experienced a partial response (90). These results suggest that AMPs may have significant therapeutic potential, particularly when combined with other immunotherapies. However, it’s important to note that larger-scale, late-stage clinical trials are needed to confirm these findings and establish the true efficacy of AMPs in cancer treatment. The field also faces challenges in optimizing delivery methods, reducing potential systemic toxicity, and overcoming regulatory hurdles In conclusion, while the clinical development of AMPs for cancer therapy is still in its early stages, the ongoing trials and preliminary results offer promising avenues for future research and potential new treatment options for cancer patients. The diverse range of AMPs being investigated, from naturally derived peptides like LL-37 to synthetic variants like LTX-315, highlights the versatility of this approach. As research progresses, it will be crucial to address challenges such as peptide stability, targeted delivery, and potential immunogenicity to fully realize the therapeutic potential of AMPs in cancer treatment.

The development of antimicrobial peptides (AMPs) for clinical application in cancer therapy faces several challenges that must be addressed to translate these promising agents into effective treatments. Key issues include stability, delivery, and potential toxicity, each of which poses significant hurdles for the successful clinical use of AMPs.

Single-Agent Therapy involves the use of a single therapeutic agent, in this case, antimicrobial peptides (AMPs), as standalone agents for cancer treatment. This approach leverages the unique properties of AMPs, such as their direct cytotoxicity and ability to modulate the immune response, to target and eliminate cancer cells.

The potential of different AMP classes for specific cancer types is an area of active research. For instance, certain cationic AMPs, known for their membrane-disrupting activity, have shown efficacy in treating solid tumors with high levels of negatively charged phospholipids on their cell surfaces. Examples include α-helical peptides like melittin and magainin, which have been investigated for their anticancer effects in breast, prostate, and colon cancers.

Other AMP classes, such as defensins and cathelicidins, exhibit additional mechanisms of action beyond membrane disruption. These peptides can induce apoptosis, modulate the immune response, and interact with intracellular targets, making them suitable for a broader range of cancer types. For example, α-defensins have been studied for their potential in treating hematological malignancies, while LL-37, a cathelicidin peptide, has shown promise in melanoma and glioblastoma.

The use of AMPs as Single-Agent Therapy offers several advantages, including their broad-spectrum activity, potential for reduced resistance, and ability to target multiple pathways within cancer cells. However, challenges such as stability, delivery, and potential toxicity must be addressed to optimize their efficacy and safety as standalone agents (93–96).

Combination therapy involves the use of AMPs in conjunction with other cancer therapies, such as chemotherapy, radiotherapy, and immunotherapy. This approach aims to exploit synergistic effects and enhance the overall efficacy of treatment regimens.

The rationale for combining AMPs with other therapies is based on their complementary mechanisms of action. For example, AMPs can enhance the cytotoxic effects of chemotherapy by disrupting tumor cell membranes and facilitating the entry of chemotherapeutic agents into cancer cells. Similarly, AMPs can potentiate the effects of radiotherapy by inducing apoptosis and modulating the tumor microenvironment, thereby improving the response to radiation.

In the context of immunotherapy, AMPs can stimulate the immune system to recognize and eliminate cancer cells. By activating pattern recognition receptors and modulating immune cell function, AMPs can enhance the efficacy of checkpoint inhibitors and other immunotherapeutic agents. Preclinical studies have demonstrated synergistic effects when AMPs are combined with immunotherapy, leading to improved tumor regression and survival rates.

Clinical evidence supporting the benefits of AMP combination therapies is emerging. Early-phase clinical trials have shown promising results, with some patients experiencing enhanced tumor responses and prolonged survival when AMPs are used in combination with conventional therapies. These findings highlight the potential of AMP combination therapies to improve treatment outcomes and overcome resistance mechanisms in cancer (97–100).

Targeted drug delivery involves the use of AMPs as delivery vehicles to specifically target cancer cells and enhance the efficiency of drug delivery. This approach leverages the natural properties of AMPs, such as their ability to bind to and penetrate cancer cell membranes, to deliver therapeutic payloads directly to tumor cells.

AMPs can be engineered to carry cytotoxic agents, imaging contrast agents, or therapeutic genes, allowing for targeted and controlled release within cancer cells. For example, AMPs can be conjugated with chemotherapeutic drugs, such as doxorubicin or paclitaxel, to create peptide-drug conjugates that selectively deliver the drugs to tumor cells. These conjugates can reduce systemic exposure to the drugs, minimizing side effects and improving the therapeutic index.

Additionally, AMPs can be engineered to target specific receptors or surface markers overexpressed on cancer cells. By incorporating targeting ligands, such as monoclonal antibodies or small molecules, into the AMP structure, the peptide can be directed to bind preferentially to cancer cells, enhancing its specificity and efficacy. This targeted approach can also reduce off-target effects and improve the overall safety profile of the therapy.

In summary, the applications of AMPs in cancer therapy encompass Single-Agent Therapy, combination therapy, and targeted drug delivery. Each approach leverages the unique properties of AMPs to enhance their anticancer effects and improve treatment outcomes. By addressing challenges related to stability, delivery, and potential toxicity, and by exploring innovative strategies such as combination therapies and targeted drug delivery, AMPs have the potential to become valuable agents in the fight against cancer (101–105).

This review has highlighted the promising potential of antimicrobial peptides (AMPs) as cancer therapeutics. Key findings from preclinical studies and early-phase clinical trials indicate that AMPs exhibit direct cytotoxicity, modulate the immune response, and can target the tumor microenvironment, making them valuable agents in the fight against cancer. The diverse mechanisms of action of AMPs, coupled with their broad-spectrum activity and potential for reduced resistance, position them as a novel class of anticancer therapeutics with significant advantages over conventional treatments.

Several critical areas for future research in AMP development have been identified to fully realize their potential as effective cancer therapies. These include:

Optimization of AMP Properties: Further research is needed to optimize the structural and functional properties of AMPs to enhance their stability, selectivity, and efficacy. This can involve structural modifications, such as altering peptide sequences, introducing chemical modifications, or engineering fusion proteins, to improve their resistance to proteolytic degradation and reduce potential toxicity.

Development of Novel Delivery Strategies: The development of advanced delivery systems is crucial for improving the targeting and efficacy of AMPs while minimizing systemic exposure. Novel delivery strategies, such as nanotechnology-based approaches, liposomes, and polymeric carriers, can enhance the delivery of AMPs to tumors and reduce off-target effects. Additionally, targeted delivery systems that incorporate specific ligands to preferentially bind to cancer cells can improve the specificity and efficacy of AMP therapy.

Exploration of Synergistic Combination Therapies: The use of AMPs in combination with other therapeutic modalities, such as chemotherapy, radiotherapy, and immunotherapy, offers a promising strategy to enhance their efficacy. Future research should focus on identifying optimal combination regimens and exploring the synergistic effects of these therapies. Preclinical and clinical studies should be conducted to assess the safety, efficacy, and clinical benefit of AMP combination therapies.

In conclusion, the significant potential of AMPs to revolutionize cancer treatment and improve patient outcomes cannot be overstated. With ongoing research and development efforts focused on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies, AMPs have the potential to become valuable agents in the fight against cancer. By addressing the challenges associated with AMP development and leveraging their unique properties, we can advance the field of cancer therapy and provide new hope for patients in need of effective and targeted treatments.