Polysaccharide-based anticancer therapeutics: molecular mechanisms, translational advances, and the road toward...

Polysaccharides comprise a structurally varied class of natural macromolecules found in plants, fungi, animals, marine algae, and microorganisms. Therefore, they have attracted considerable attention over several decades due to numerous anticancer-associated activities indicated by accumulating in vitro and in vivo evidence, along with clinical data of heterogeneous maturity-ranging from well-established adjuvants such as lentinan and PSK, which have demonstrated survival benefits in randomized controlled trials, to early-phase exploratory studies for agents like fucoidan. Traditional chemotherapeutic agents (e.g., alkylating agents, antimetabolites) exert direct cytotoxic effects; however, many contemporary small-molecule drugs-such as kinase inhibitors and hormone receptor modulators-act through targeted inhibition of oncogenic signaling, and immunotherapies (e.g., checkpoint inhibitors) function by enhancing endogenous anti tumor immunity rather than directly damaging tumor cells, as cytotoxic agents do. By contrast, polysaccharides are increasingly recognized as biological response modifiers that exert an impact on cancer development through, for instance, immune system functioning, redox, and/or inflammatory balance, communications between cancer and stromal cells of the tumor microenvironment, and intracellular signaling cascades. This review presents an outline of the structural variability, physiological sources, and functions of polysaccharides relevant to cancer treatment. Based on the present armamentarium of polysaccharides, the main modes of action are summarized in terms of immunomodulation through the engagement of pattern-recognition receptors, oxidative stress and inflammation regulation, quantifiable programmed cell death modes, angiogenesis and metastasis, and indirect regulation of oncogenic signaling pathways. These are first expressed in terms of the target-unrelated context and at the network level. Finally, we briefly discuss recent developments regarding polysaccharides as coadjuvants in chemotherapy, radiotherapy, and immunotherapy, in addition to their status as potential biomaterials in novel drug delivery systems. Critical reviews of relevant issues regarding structural heterogeneity and reproducibility, pharmacokinetics, and clinical translation are given. Indeed, this review presents polysaccharides as multi-functional components in multi-dimensional cancer therapy, paying due attention to appropriate structural elucidation, mechanism validation, and systems-oriented approaches to their rational development and clinical application.