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mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor

Priyatosh Nath1, Alok Khandelwal2, Chun Li1

  • 1Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, LA, 71103, USA.

Neoplasia (New York, N.Y.)
|August 8, 2026
PubMed

Insights

mTOR inhibition with everolimus overcomes immune resistance in TP53-mutant head and neck squamous cell carcinoma (HNSCC) by enhancing anti-tumor T cell activity and reprogramming the tumor microenvironment (TME). This strategy shows promise for patients resistant to immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • TP53-mutant head and neck squamous cell carcinoma (HNSCC) exhibits immune exclusion, leading to resistance to immunotherapy, high recurrence rates, and poor patient outcomes.
  • Constitutive activation of the PI3K/AKT/mTOR signaling pathway is prevalent in TP53-mutant HNSCC and contributes to disease progression.
  • Understanding the mechanisms of immune resistance in HNSCC is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate whether mTOR inhibition (mTORi) can overcome immune resistance and improve outcomes in TP53-mutant HNSCC.
  • To evaluate the effects of the mTOR inhibitor everolimus on the tumor microenvironment (TME), including immune cell infiltration and immune checkpoint expression.
  • To define the mechanisms by which everolimus remodels the TME and enhances anti-tumor immunity.

Main Methods:

  • Evaluation of everolimus in syngeneic HNSCC models.
  • Analysis of tumor microenvironment changes: immune cell infiltration (CD8+ T cells, dendritic cells, regulatory T cells), immune checkpoint expression (PD-1/PD-L1), and key pathway modulation (PI3K/AKT/mTOR, HIF-1α/VEGFA).
  • Assessment of cytokine/chemokine profiles (TNF-α, CXCL10) and myeloid-derived suppressor cell (MDSC) recruitment.

Main Results:

  • Everolimus significantly suppressed tumor growth and increased intratumoral CD8+ T cell and dendritic cell infiltration while decreasing regulatory T cell accumulation.
  • Mechanistically, everolimus induced TNF-α/CXCL10 expression, enhancing immune cell infiltration, and inhibited the HIF-1α/VEGFA pathway, reducing immune exclusion and MDSC recruitment.
  • Everolimus treatment attenuated PD-1/PD-L1 signaling, restoring T-cell cytotoxic activity.

Conclusions:

  • mTOR inhibition with everolimus reverses multiple mechanisms of immune resistance in TP53-mutant HNSCC.
  • Everolimus enhances anti-tumor T cell activity by reprogramming the immune-resistant tumor microenvironment.
  • mTORi represents a rational therapeutic strategy for TP53-mutant HNSCC, particularly for patients predicted to be resistant to immunotherapy.
Keywords:
EverolimusHead and neck squamous cell carcinoma (HNSCC)TP53 mutationTumor immunityTumor microenvironment (TME)mTOR

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