Head and neck squamous cell carcinoma (HNSCC) is a group of cancers arising in the oropharyngeal and laryngeal regions. Lifestyle choices such as smoking, tobacco chewing, alcohol consumption, and human papillomavirus (HPV) infection are key risk factors. Therapeutic options include surgical resection, chemoradiotherapy, EGFR-targeting therapy, and immunotherapy. However, the treatments are limited by drug resistance, relapses, and poor response to immunotherapy, especially in advanced diseases. The difference in tissue types and HPV infection status may lead to significant variations in their tumor microenvironment (TME). The heterogeneity contributes to poor treatment response and the development of therapeutic resistance. Therefore, it is critical to have a deeper understanding of the complexities and heterogeneity in TME and its role in treatment resistance. In this review, we focused on tumor heterogeneity and the role of cancer and non-cancer cells in therapeutic resistance. We discussed the studies on human HNSCC, especially HPV-negative, and presented the diversity in the tumor microenvironment and treatment response. Furthermore, we address the existing and experimental therapeutics that target therapy resistance and may lead to a better understanding of the disease and improve therapeutic outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a major global health burden, often associated with poor prognosis and limited therapeutic options. Long non-coding RNAs (lncRNAs), a diverse group of non-coding RNA molecules > 200 nucleotides in length, have emerged as critical regulators in the pathogenesis of HNSCC. This review summarizes the mechanisms through which certain lncRNAs regulate chromatin modification, mRNA splicing, and interactions with RNA-binding proteins and contribute to the development and progression of HNSCC. Interaction of lncRNAs with key oncogenic pathways, such as PI3K/AKT and Wnt/β-catenin, highlights their importance in tumor progression. The role of lncRNAs, such as ELDR, MALAT1, NEAT1, HOTAIR, and UCA1, which promote cell proliferation, metastasis, immune evasion, and therapy resistance is discussed. Moreover, several lncRNAs are being evaluated in clinical trials for their potential as biomarkers, reflecting their clinical significance. We further address the challenges and opportunities for targeting lncRNA therapeutically, highlighting the promise of lncRNA-based interventions for personalized cancer treatment. Gaining insight into the function of lncRNAs in HNSCC could pave the way for novel therapeutic strategies to potentially improve patient outcomes.

TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy.

[This retracts the article DOI: 10.1016/j.isci.2022.104325.].

Nepal aims to eliminate lymphatic filariasis (LF) by 2030. Mass drug administration (MDA) has ceased in 53 of the 64 endemic districts. Following failure to pass the pre-Transmission Assessment Survey of antigenemia prevalence, five districts completed two rounds of MDA using a three-drug regimen (Ivermectin, Diethylcarbamazine, and Albendazole; IDA) and achieved over 65% coverage of the total population in 2023 and 2024. An Epidemiological Monitoring Survey (EMS) was conducted to evaluate IDA’s impact. A cross-sectional EMS was conducted 9 months post-MDA in 11 evaluation units (EUs) across five districts, using two sites per EU (n = 22). A total of 6,829 individuals aged ≥20 years were sampled via multi-stage methods, with ≥300 blood samples per site. Data on demographics and MDA participation were collected. LF antigen testing was followed by night blood microfilariae testing in antigen-positive samples. Analysis included non-parametric tests, logistic and mixed-effects models accounting for site-level clustering, and penalized regression (lasso and ridge) to assess predictor importance and manage multicollinearity. Nine of 11 EUs passed EMS. Two EUs in Kapilvastu failed due to ≥1% microfilariae prevalence in at least one site. Microfilariae prevalence was negatively correlated with site MDA coverage (p-value 0.04), but not antigen prevalence (p-value 0.8). Overall, 4.63% of participants were antigen-positive and 0.34% were microfilariae-positive (ratio 14:1). Being female (OR 0.12; 95% CI: 0.04-0.36) and participation in latest MDA round (OR 0.34; 95% CI: 0.15-0.77) were associated with lower microfilariae prevalence. Suboptimal impact of MDA was observed in two EUs based on microfilariae prevalence and may reflect insufficient treatment compliance. Two additional rounds of MDA with directly observed treatment are recommended to improve adherence. Female sex and participation in the most recent MDA round were associated with reduced odds of microfilaremia. Targeted strategies focusing on men and other identified risk groups may enhance program effectiveness.