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HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%–22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.

Accumulating evidence suggests the immunosuppressive microenvironments created by malignant tumors represent a major obstacle for effective anti‐tumor immunity. A better understanding of the suppressive mechanisms mediated by tumor microenvironments and the development of strategies to reverse the immune suppression are major challenges for the success of tumor immunotherapy. Here, we report that human tumor cells can induce senescence in naïve/effector T cells, exhibiting potent suppressive function in vitro and in vivo . We further show that tumor‐derived endogenous cyclic adenosine monophosphate (cAMP) is responsible for the induction of T‐cell senescence. Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naïve and tumor‐specific T cells in vitro and in vivo , resulting in enhanced anti‐tumor immunity. These studies identify a novel mechanism of human tumor‐mediated immune suppression and provide a new strategy to reverse tumor immunosuppressive effects for tumor immunotherapy. Synopsis This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy. Tumor cells convert naïve/effector T cells into senescent T cells with potent suppressive function. Tumor‐derived cAMP is responsible for the tumor cell‐induced T‐cell senescence. cAMP is directly transferred from tumor cells to targeted T cells through gap junctions inducing PKA‐LCK inhibitory signaling and senescence in T cells. TLR8 signaling reverses tumor‐induced T‐cell senescence via down‐regulation of cAMP in tumor cells. Activation of TLR8 signaling in tumor cells prevents tumor‐specific T‐cell senescence and enhances anti‐tumor immunity. Graphical Abstract This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

Background SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown. Methods We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions. Results We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways. Conclusion Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells.

ACC is a rare malignant tumor of the salivary glands. In this contemporary review, we explore advances in identification of targetable alterations and clinical trials testing these druggable targets. A search of relevant articles and abstracts from national meetings and three databases, including PubMed, Medline, and Web of Science, was performed. Following keyword search analysis and double peer review of abstracts to ensure appropriate fit, a total of 55 manuscripts were included in this review detailing advances in molecular targets for ACC. The most researched pathway associated with ACC is the MYB–NFIB translocation, found to lead to dysregulation of critical cellular pathways and thought to be a fundamental driver in a subset of ACC disease pathogenesis. Other notable molecular targets that have been studied include the cKIT receptor, the EGFR pathway, and NOTCH1, all with limited efficacy in clinical trials. The ongoing investigation of molecular abnormalities underpinning ACC that may be responsible for carcinogenesis is critical to identifying and developing novel targeted therapies.

To characterize smoking and alcohol use, and to describe predictors of oral cancer knowledge among a predominantly African-American population. A cross-sectional study was conducted between September, 2013 among drag racers and fans in East St. Louis. Oral cancer knowledge was derived from combining questionnaire items to form knowledge score. Covariates examined included age, sex, race, marital status, education status, income level, insurance status, tobacco and alcohol use. Adjusted linear regression analysis measured predictors of oral cancer knowledge. Three hundred and four participants completed questionnaire; 72.7% were African Americans. Smoking rate was 26.7%, alcohol use was 58.3%, and mean knowledge score was 4.60 ± 2.52 out of 17. In final adjusted regression model, oral cancer knowledge was associated with race and education status. Compared with Caucasians, African Americans were 29% less likely to have high oral cancer knowledge (β = -0.71; 95% CI: -1.35, -0.07); and participants with a high school diploma or less were 124% less likely to have high oral cancer knowledge compared with college graduates (β = -1.24; 95% CI: -2.44, -0.41). There was lower oral cancer knowledge among African Americans and those with low education. The prevalence of smoking was also very high. Understanding predictors of oral cancer knowledge is important in future design of educational interventions specifically targeted towards high-risk group for oral cancer.

One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1 , PFKP , PDK3 , PKM , and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY , ACC1 , FASN , SREBP1 , and SCD1 . Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications. Graphical Abstract

Objective To evaluate for correlation between intraoperative ultrasound (IOUS)‐measured tumor thickness (TT) (uTT) and histopathological TT (hTT), and to compare IOUS‐assisted resection with conventional resection in patients with oral tongue cancers. Data Sources Ovid MEDLINE (1946‐2023), Embase.com (1947‐2023), and Web of Science (All Databases 1900‐2023). Review Methods Inclusion criteria were the use of IOUS for the management of oral tongue cancer. Studies that did not report quantitative data were excluded. Additionally, studies that were not contributory to meta‐analysis, or a narrative analysis of pooled results were excluded. Selection was carried out by 2 reviewers. A total of 2417 studies were initially identified, with 12 ultimately being included in this review, and 7 included in the meta‐analysis. Data were extracted by 2 investigators and were pooled using a random‐effects model. Results Our meta‐analysis reveals a pooled correlation coefficient of 0.92 (95% confidence interval: 0.80‐0.96) for studies comparing uTT to hTT. Studies comparing IOUS‐assisted resection to conventional resection found IOUS‐assisted resection yielded wider nearest margins in all studies reporting this outcome. Conclusion IOUS reliably measures TT, similarly to that of histopathology measurement. IOUS‐assisted resection, which allows the surgeon to view the deep extent of tumor invasion, may increase closest radial margin distance compared to conventional resection. IOUS‐assisted resection may represent a more reliable approach to achieving clear margins than conventional resection.

Objectives To describe a 10‐year single center experience with parotid gland malignancies and to determine factors affecting outcomes. Study Design Retrospective review. Methods The institutional cancer registry was used to identify patients treated surgically for malignancies of the parotid gland between January 2005 and December 2014. Clinical and pathologic data were collected retrospectively from patient charts and analyzed for their association with overall survival (OS) and disease‐free survival (DFS). Results Two hundred patients were identified. Mean age at surgery was 57.8 years, and mean follow‐up time was 52 months. One hundred two patients underwent total parotidectomy, while 77 underwent superficial parotidectomy, and 21 underwent deep lobe resection. Seventy patients (35%) required facial nerve (FN) sacrifice. Acinic cell carcinoma was the most common histologic type (22%), followed by mucoepidermoid carcinoma (21.5%) and adenoid cystic carcinoma (12.5%). Twenty‐nine patients (14.5%) experienced recurrences, with mean time to recurrence of 23.6 months (range: 1‐82 months). Five‐ and 10‐year OS were 81% and 73%, respectively. Five‐ and 10‐year DFS were 80% and 73%, respectively. In univariate analyses, age > 60, histologic type, positive margins, high grade, T‐stage, node positivity, perineural invasion, and FN involvement were predictors of OS and DFS. In the multivariate analysis, histology, positive margins, node positivity, and FN involvement were independent predictors of OS and DFS. Conclusions Our single‐center experience of 200 patients suggests that histology, positive margins, node positivity, and FN involvement are independently associated with outcomes in parotid malignancies. Level of Evidence 4

Purpose To investigate the effect of race and sex on long-term survival of oral and oropharyngeal cancer. Methods The Surveillance, Epidemiology and End Results database was queried for adult oral and oropharyngeal cancer patients with at least 25-year follow-up. Kaplan–Meier survival curves and cox proportional hazards model were used to identify differences. Results Of the 22,162 patients identified, 70.3 % were males. Only 8.9 % were alive at 25 years post-diagnosis. Black males show the poorest overall and disease-specific survival rates ( p  < 0.001). After controlling for covariates, Blacks had a 40 % higher hazard of mortality compared with Whites (HR 1.40, 95 % CI 1.35–1.46), while females had a 9 % reduction in mortality risk (HR 0.91, 95 % CI 0.88–0.94). Conclusions Overall and disease-specific survival is poor for oral and oropharyngeal cancer patients, and Black men fare worst. This illustrates the need for long-term cancer survival plans incorporating disparity effects in overall cancer outcomes.