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Page 10 of 13 Fang et al. Cancer Drug Resist. 2025;8:42

Figure 6. Proposed mechanism of ROS1 mutation-driven immune evasion in HNC. HNC: Head and neck cancer; APCs: antigen-presenting
cells; ICIs: immune checkpoint inhibitors; TMB: tumor mutational burden; TME: tumor microenvironment; TNB: tumor neoantigen burden.

Therapeutically, ROS1-Mut HNC may benefit from combinatorial strategies targeting both immune evasion
pathways and oncogenic drivers. Preclinical studies show that ROS1 inhibitors (e.g., entrectinib) can reverse
oncogenic signaling [13,26] , while MYC inhibition can restore antigen presentation in other models . Thus,
[39]
combinatorial strategies represent a biologically grounded approach warranting further evaluation in
ROS1-mutant systems.

This study has limitations. ROS1 mutations occur at relatively low incidence in HNC (5%-7%), though this
subgroup exhibits significant clinical detriment (median OS: 5 months). Our biomarker claims are
constrained by the small sample size of ROS1-mutant cases (n = 7 in the ICI-treated cohort), heterogeneity of
variants (predominantly VUS), and lack of functional validation. While statistically significant, these findings
require prospective validation in larger cohorts and mechanistic studies to confirm ROS1’s role in immune
evasion. Additionally, the absence of prognostic significance in TCGA (non-ICI-treated cohort) underscores
its context-specific predictive role, akin to KRAS mutations in colorectal cancer .
[40]
In conclusion, ROS1-mutant HNC defines a molecular subset with intrinsic ICI resistance driven by
MYC-mediated immunosuppression. If validated prospectively, integrating ROS1 status with TMB and
PD-L1 expression could optimize patient stratification for ICI therapy, though further studies are essential to
establish clinical utility.

DECLARATIONS
Acknowledgments
The authors kindly thank Dr. Xing Zhang (Jiangsu Simcere Diagnostics Co., Ltd.) for providing professional
technical support for this research.

Authors’ contributions
Writing - original draft, validation: Fang C
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