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Head and neck squamous cell carcinoma (HNSCC) remains a challenge due to limited prognostic biomarkers and therapeutic options. The tumor microenvironment (TME), particularly the desmoplastic reaction (DR) characterized by stromal fibrosis, plays a crucial role in cancer progression and resistance to therapy. This review aims to summarize the biological significance of DR in HNSCC initiation, progression, and treatment resistance. Histologically, DR in HNSCC correlates with invasion patterns and clinical outcomes, affecting disease-free and overall survival. The interaction between cancer-associated fibroblasts (CAFs) and TME influences immune responses, including resistance to immunotherapy. Notably, human papillomavirus-driven HNSCC exhibits distinct DR characteristics that further influence the prognosis. DR promotes epithelial-mesenchymal transition and cancer cell invasion through CAF-mediated extracellular matrix remodeling and signaling pathways such as transforming growth factor-beta. DR also affects bone invasion and chemotherapy resistance by modulating stromal responses. Therapeutic strategies targeting DR and stromal components show promise in overcoming therapeutic resistance including resistance to immune checkpoint inhibitors. Understanding the role of DR in HNSCC biology and its impact on treatment response is critical to developing effective therapeutic interventions.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to immunotherapy. The interplay between β‐adrenergic signaling and p53 loss, both key regulators of immune responses, has remained largely unexplored in the setting of tumor‐immune evasion. This study demonstrates that pharmacologic stimulation of β2‐adrenergic receptors with isoprenaline significantly enhances cytotoxic T cell activity against p53‐deficient HNSCC cells via a CXCL10‐dependent paracrine mechanism. Comprehensive transcriptomic and co‐culture assays reveal that p53‐null cancer cells upregulate CXCL10, which promotes CD8+ T cell recruitment and activation. Neutralization of CXCL10 abolishes the β‐adrenergic‐induced cytotoxic T cell response, establishing this chemokine as a pivotal mediator. Using tyrosine hydroxylase knockout mouse models, we show that adrenergic innervation is essential for intra‐tumoral CXCL10 expression and the infiltration of effector CXCR3+ T cells in vivo. Notably, the CXCL10‐driven T cell response is associated with simultaneous upregulation of both activation and exhaustion markers, indicating a robust but transient effector state within the tumor microenvironment. Collectively, these findings uncover a neuro‐immune axis that reverses immune escape in p53‐deficient HNSCC and suggest novel therapeutic strategies targeting adrenergic signaling to convert immune “cold” tumors into “hot” ones more amenable to immunotherapy. β‐adrenergic stimulation enhances anti‐tumor immunity in TP53‐deficient oral squamous cell carcinoma by inducing tumor‐derived secretion of CXCL10, which attracts and activates cytotoxic CD8+ T cells. The findings demonstrate that β‐adrenergic signaling alters tumor–immune interactions via CXCL10‐mediated paracrine activation, revealing a neuro‐immune axis that overcomes immune escape in p53‐deficient tumors.

The present review aimed to elucidate the roles of extracellular matrix (ECM) components in the progression of vulvar squamous cell carcinoma (VSCC) and explore potential therapeutic avenues for this type of malignancy. This exploration holds promise for identifying precise molecular targets within the ECM milieu, thus facilitating the development of innovative therapeutic modalities tailored to disrupt these interactions and ultimately improve patient outcomes in VSCC. The dysregulated ECM serves as a potent driver of SCC tumor progression, orchestrating key processes such as angiogenesis, inflammation and stromal cell behavior. Yet, the exploration of ECM role in VSCC is still in its early stages. Recent research highlights the critical role of ECM organization and expression within the tumor microenvironment (TME) in influencing key aspects of VSCC, including tumor staging, grading, metastasis, invasion and patient survival. Cancer-associated fibroblasts play a pivotal role in this dynamic by engaging in reciprocal interactions with VSCC cells, leading to significant ECM alterations and creating an immune-suppressive TME. This hinders antitumor immunity and fosters therapeutic resistance in VSCC treatment. The dysregulated ECM in VSCC drives tumor progression, metastasis and affects patient survival. Targeting ECM, along with emerging therapies such as immune checkpoint blockade, offers promise for improved VSCC treatment outcomes.

Background: Knowledge on the role of miR changes in tumor stroma for cancer progression is limited. This study aimed to investigate the role of miR dysregulation in cancer-associated fibroblasts (CAFs) in oral squamous cell carcinoma (OSCC). Methodology: CAF and normal oral fibroblasts (NOFs) were isolated from biopsies of OSCC patients and healthy individuals after informed consent and grown in 3D collagen gels. Total RNA was extracted. Global miR expression was profiled using Illumina version 2 panels. The functional impact of altered miR-204 expression in fibroblasts on their phenotype and molecular profile was investigated using mimics and inhibitors of miR-204. Further, the impact of miR-204 expression in fibroblasts on invasion of adjacent OSCC cells was assessed in 3D-organotypic co-cultures. Results: Unsupervised hierarchical clustering for global miR expression resulted in separate clusters for CAF and NOF. SAM analysis identified differential expression of twelve miRs between CAF and NOF. Modulation of miR-204 expression did not affect fibroblast cell proliferation, but resulted in changes in the motility phenotype, expression of various motility-related molecules, and invasion of the adjacent OSCC cells. 3′ UTR miR target reporter assay showed ITGA11 to be a direct target of miR-204. Conclusions: This study identifies differentially expressed miRs in stromal fibroblasts of OSCC lesions compared with normal oral mucosa and it reveals that one of the significantly downregulated miRs in CAF, miR-204, has a tumor-suppressive function through inhibition of fibroblast migration by modulating the expression of several different molecules in addition to directly targeting ITGA11.