Comment on “Sennoside A Modulates the Ferroptosis and Immune Evasion of Oral Squamous Cell Carcinoma Cells Through Inhibiting the NF-κB Pathway”

Dear Editor,

We read with great interest the study by Huo et al ¹ examining the role of sennoside A (SA) in ferroptosis and immune evasion in oral squamous cell carcinoma (OSCC). The authors are commended for integrating in vitro and in vivo models and anchoring their mechanistic work to the clinically relevant NF-κB pathway, a signaling axis with implications for both therapeutic sensitivity and immune responsiveness.

Although the findings are compelling, several aspects of the study design and interpretation invite caution regarding translation into patient care. The concentration response relationship is central to clinical applicability. In CAL27 and SCC7 cells, the reported half-maximal inhibitory concentration values of 77 to 94 μM are considerably higher than the nanomolar range achievable with existing OSCC therapeutics. This discrepancy raises the possibility that the observed ferroptosis and PD-L1 modulation reflect supraphysiologic exposure. ² The clinical feasibility of SA as a therapeutic candidate remains uncertain without pharmacokinetic data or dose-ranging animal experiments beyond a single intraperitoneal regimen. From a patient perspective, an agent requiring concentrations several orders above physiological tolerance may not be a viable addition to treatment algorithms.

The statistical approach, although standard for cellular assays, warrants refinement when paired with claims of immune modulation. For example, Student’s t-tests applied to repeated cytokine measures across IFN-γ, IL-2, and TNF-α, introduce a high false-positive risk. More rigorous adjustment for multiplicity is expected, particularly because these cytokines are used as clinical biomarkers of T-cell activity in immuno-oncology trials. Misinterpretation of immune activation on statistical grounds could lead to premature expectations regarding synergy with checkpoint inhibitors, where treatment decisions depend on reproducible biomarker shifts. ³

Furthermore, the reliance on murine xenografts with subcutaneous tumor implantation, although a well-established model, limits inferences about immune evasion in OSCC. Human tumors exhibit microenvironmental features, such as mucosal immunity and antigen presentation, that are not faithfully recapitulated in BALB/c nude mice. Therefore, the claim of improved CD8+ T-cell cytotoxicity should be interpreted within this model constraint; otherwise, clinicians might infer efficacy in immunocompetent patients, where the tumor–host interaction is more complex. ⁴

Despite these concerns, the work remains valuable in pointing to NF-κB as a convergent target linking ferroptosis regulation and immune checkpoint control in OSCC. This conceptual framework can inform future investigations of pharmacologically achievable and statistically robust drug combinations. We encourage the authors to expand on these translational aspects, as dialogue between the laboratory and clinical domains is essential to advance patient-centered therapies for OSCC.

Manish R. BhiseDepartment of Pharmaceutics, SGSPS, Institute of Pharmacy, Sant Gadge Baba Amravati University, Akola, India Mohd Hasib AhmedKarmayogi Tatyasaheb Bondre Institute of Pharmacy, Chikhli, India Sanjay N. VasuMahatma Phule Pharmacy College Akola, Sant Gadge Baba Amravati University, Akola, India