Cancer remains one of the most formidable challenges in modern medicine, claiming roughly one in nine men and one in twelve women worldwide. Despite decades of progress in surgery, chemotherapy, radiotherapy and the more recent wave of immunotherapies, many current treatments carry debilitating side effects, and a substantial fraction of patients either fail to respond or develop resistance. Against this backdrop, a new review published in Molecular Biology Reports by researchers at the SRM Institute of Science and Technology in India makes the case that some of the most powerful allies in the fight against cancer may already exist in nature. The review, led by Title De, Roshni Bibi and Koustav Sarkar, surveys the landscape of natural adjuvants, biologically derived substances that can amplify or reshape the immune response, and argues that these compounds deserve a central place in the next generation of cancer immunotherapies.
The concept of an adjuvant is not new. Adjuvants are agents administered alongside antigens to boost the quality, magnitude or duration of an immune response. Aluminum-based salts have dominated vaccine formulation for nearly a century, and the field’s origins trace back even further, to William B. Coley’s late nineteenth-century experiments with bacterial toxins to treat sarcomas. What has changed is the sophistication with which scientists can now dissect how adjuvants work at the molecular level. Modern immunology has revealed that effective adjuvants do far more than simply irritate the immune system into action. They promote the activation and maturation of antigen-presenting cells, the dendritic cells and macrophages that patrol tissues and sample their surroundings for danger. Once activated, these cells process tumor or vaccine antigens and display fragments of them on major histocompatibility complex molecules, the molecular billboards that cytotoxic T lymphocytes must read before they can kill a target cell.
This is precisely where natural adjuvants show their strength, according to the review. Compounds extracted from plants, microorganisms and animals can stimulate the signaling pathways that govern cytokine production and T-cell activation, effectively converting a weak or tolerogenic encounter with a tumor antigen into a robust, cell-killing immune response. The authors emphasize that natural products offer remarkable structural diversity and a broad repertoire of biological activities, qualities that synthetic chemists have long tried to emulate. Yet the review is equally candid about the caveats: chemical inertness, batch-to-batch variability, and safety must be rigorously evaluated and standardized before these compounds can be deployed in the clinic. Evidence quality also varies considerably across cancer types and experimental systems, a point the authors stress rather than gloss over.
Among the plant-derived candidates, few have attracted as much sustained attention as neem leaf glycoprotein, a compound with an unusually well-documented immunological dossier. Studies spanning nearly two decades have shown that neem leaf glycoprotein can drive carcinoembryonic antigen-specific anti-tumor immune responses by harnessing macrophage-mediated antigen presentation. More recent work has illuminated the mechanism in striking detail: the glycoprotein binds to Dectin-1 receptors on dendritic cells, triggering a CARD9-mediated intracellular signaling cascade that activates the transcription factor NF-kappaB and skews the immune system toward a type-1, cell-mediated response, the arm of immunity most effective against tumors. Additional preclinical studies suggest the glycoprotein can counterbalance the immunosuppressive effects of tumor-associated mesenchymal stem cells, restore exhausted CD8-positive T-cell function against cancer stem cells, and even delay chemically induced oral carcinogenesis in mouse models.
Polysaccharides form another major pillar of the natural adjuvant repertoire. Beta-glucans, long chains of glucose found in fungal cell walls, have emerged as agonists of Toll-like receptors and inducers of macrophage anti-cancer activity, with recent work on polysaccharides from the mushroom Inonotus obliquus, better known as chaga, demonstrating this receptor-level engagement directly. Plant polysaccharides, meanwhile, are being explored for their ability to reprogram macrophage polarization, shifting tumor-associated macrophages from a pro-tumor, M2-like state toward an anti-tumor, M1-like phenotype. Because tumor-associated macrophages often constitute a large fraction of the tumor mass and actively promote chemoresistance and metastasis, agents capable of flipping their allegiance represent a strategically important class of immunomodulators. Polysaccharides such as those from Angelica sinensis have even been encapsulated into PLGA nanoparticles, demonstrating how ancient remedies can be repackaged with cutting-edge delivery technology to serve as combined vaccine adjuvant and antigen-delivery systems.
The microbial world contributes its own arsenal. Bacterial flagellin, the protein that builds the whip-like appendages of motile bacteria, is a potent agonist of Toll-like receptor 5 and has been engineered into Salmonella typhimurium strains that secrete the molecule to enhance cancer immunotherapy in two-step treatment regimens. Structural biologists are now mapping the minimal domains of flagellin required for TLR5 activation, seeking to strip away immunodominant regions that could provoke unwanted responses while preserving the adjuvant signal, a process known as deimmunization that is considered essential for clinical translation. Bacterial ghosts, the empty cell envelopes of lysed bacteria, and virosomes, engineered virus-like particles, round out the microbial toolkit as delivery platforms that combine antigen carriage with built-in immune stimulation.
Animal-derived compounds add yet another dimension. Bee venom and its principal component melittin have shown the ability to synergize with conventional drugs such as sorafenib against hepatocellular carcinoma cells, and melittin-incorporated nanomedicines are now being developed to harness its cytolytic power while taming its toxicity for enhanced cancer immunotherapy. Silk sericin, the protein that glues silk fibers together, is being investigated as a sustainable biomaterial with immunoregulatory effects on inflammatory pathways, while chitosan, derived from crustacean shells, and its quaternized derivative trimethyl chitosan have established track records as mucosal vaccine adjuvants and nanoparticulate delivery carriers. Saponins, both natural and synthetic, occupy a special place in the adjuvant pantheon, with molecules such as tomatine from tomatoes contributing to the growing family of carbohydrate-based immune stimulants whose mechanisms of action are increasingly well understood.
What unites these disparate compounds is their potential role in cancer vaccines and combination regimens. Depending on formulation, natural adjuvants can serve as components of drug or antigen-delivery systems, be incorporated directly into vaccine production, or act as adjuncts that sensitize tumors to checkpoint inhibitors targeting the PD-1/PD-L1 axis. The review highlights applications across breast cancer, melanoma, liver cancer and prostate cancer, while noting honestly that the strength of supporting evidence differs among these indications. The convergence with nanotechnology is particularly striking: lipid nano drug delivery systems based on traditional Chinese medicine, plant-derived immunomodulatory nanoadjuvants, and beta-glucan-based immunocyte-targeting vehicles all illustrate how natural compounds are being engineered into precisely controlled formulations that can ferry antigens to dendritic cells while simultaneously providing the danger signals those cells need to mount a response.
Challenges remain formidable. The review’s authors are careful to note that natural products can suffer from chemical complexity that complicates standardization, potential toxicity that must be quantified, and mechanisms of action that are sometimes only partially understood, as is the case for the polysaccharide adjuvant inulin, whose mode of action remains elusive despite demonstrated efficacy. Regulatory pathways designed for single, well-defined molecules must adapt to multi-component natural extracts. Clinical evidence, while growing, still lags behind the preclinical enthusiasm, and the historical record of cancer immunotherapy is littered with approaches that worked brilliantly in mice but faltered in humans. The randomized phase III MIND-DC trial of dendritic cell therapy in melanoma, cited in the review, exemplifies both the promise and the difficulty of translating immunological theory into survival benefit.
Nevertheless, the trajectory of the field is unmistakable. From Coley’s crude bacterial toxins to Dectin-1 agonists engineered at the level of individual signaling domains, natural adjuvants have evolved from folk remedies into rationally designed components of sophisticated immunotherapeutic platforms. The SRM Institute team’s synthesis makes a compelling case that plants, fungi, bacteria and animals have already solved, through billions of years of evolution, many of the problems that immunologists are now trying to crack in the laboratory. If the issues of standardization, safety evaluation and clinical validation can be resolved, natural adjuvants may well become indispensable partners to the checkpoint inhibitors, therapeutic vaccines and nanomedicines that define contemporary cancer treatment, offering patients the prospect of powerful anti-tumor immunity with fewer of the harsh side effects that have long been the price of fighting cancer.
Subject of Research: Natural product-derived immune adjuvants for cancer immunotherapy
Article Title: Empowering cancer therapy: the promise of natural adjuvants
Article References: De, T., Bibi, R., & Sarkar, K. (2026). Empowering cancer therapy: the promise of natural adjuvants. Molecular Biology Reports, 53(1), Article 1627. https://doi.org/10.1007/s11033-026-12800-z
Image Credits: AI Generated
DOI: 10.1007/s11033-026-12800-z
Keywords: cancer immunotherapy, natural adjuvants, neem leaf glycoprotein, antigen-presenting cells, polysaccharides, beta-glucan, melittin, chitosan, Toll-like receptors, dendritic cells, cancer vaccines, tumor microenvironment
