Withaferin A, a bioactive steroidal lactone derived from Withania somnifera (Ashwagandha), has gained attention for its potent immunomodulatory and anti-inflammatory properties. Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 antibodies, has revolutionized cancer treatment but is frequently associated with immune-related adverse effects (irAEs) [1], including systemic inflammation and autoimmune-like responses. Recent studies suggest that Withaferin A can regulate immune pathways by inhibiting NF-κB activation [2], suppressing pro-inflammatory cytokines (e.g., IL-6, TNF-α) [3], and restoring immune homeostasis. These mechanisms make Withaferin A a promising candidate for mitigating irAEs without compromising the anti-tumor efficacy of ICIs. Preclinical studies further highlight its ability to modulate T-cell responses and macrophage polarization, both critical in the pathogenesis of immunotherapy-induced toxicities. This review synthesizes current evidence on Withaferin A’s immunomodulatory mechanisms and discusses its potential integration as an adjunct therapy to reduce adverse effects in cancer immunotherapy. While promising, further in vivo studies and clinical trials are essential to confirm its safety, optimal dosage, and long-term impact on patient outcomes. This work underscores the importance of exploring plant-derived bioactive molecules as complementary strategies to improve the tolerability and effectiveness of cancer treatment.

References:
[1] Ramos-Casals, M., et al. (2020). Immune-related adverse events of checkpoint inhibitors. Nature Reviews Disease Primers, 6, 1-21. https://doi.org/10.1038/s41572-020-0160-6.
[2] Heyninck, K., et al. (2014). Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ.. Biochemical pharmacology, 91 4, 501-9 . https://doi.org/10.1016/j.bcp.2014.08.004.
[3] Alnuqaydan, A., et al. (2022). Evaluation of the Cytotoxic, Anti-Inflammatory, and Immunomodulatory Effects of Withaferin A (WA) against Lipopolysaccharide (LPS)-Induced Inflammation in Immune Cells Derived from BALB/c Mice. Pharmaceutics, 14. https://doi.org/10.3390/pharmaceutics14061256.