Mohsen Nabi Afjadi’s research while affiliated with Tarbiat Modares University and other places

Head and neck squamous cell carcinoma (HNSCC) remains among the most aggressive malignancies with limited treatment options, especially in recurrent and metastatic cases. Despite advances in surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitors, survival rates remain suboptimal due to tumor heterogeneity, immune evasion, and treatment resistance. In recent years, Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized hematologic cancer treatment by genetically modifying T cells to target tumor-specific antigens like CD19, CD70, BCMA, EGFR, and HER2, leading to high remission rates. Its success is attributed to precise antigen recognition, sustained immune response, and long-term immunological memory, though challenges like cytokine release syndrome and antigen loss remain. Notably, its translation to solid tumors, including HNSCC, faces significant challenges, such as tumor microenvironment (TME)-induced immunosuppression, antigen heterogeneity, and limited CAR T-cell infiltration. To address these barriers, several tumor-associated antigens (TAAs), including EGFR, HER2 (ErbB2), B7-H3, CD44v6, CD70, CD98, and MUC1, have been identified as potential CAR T-cell targets in HNSCC. Moreover, innovative approaches, such as dual-targeted CAR T-cells, armored CARs, and CRISPR-engineered modifications, aim to enhance efficacy and overcome resistance. Notably, combination therapies integrating CAR T-cells with immune checkpoint inhibitors (e.g., PD-1/CTLA-4 blockade) and TGF-β-resistant CAR T designs are being explored to improve therapeutic outcomes. This review aimed to elucidate the current landscape of CAR T-cell therapy in HNSCC, by exploring its mechanisms, targeted antigens, challenges, emerging strategies, and future therapeutic potential.

Oral cancer, a prevalent form of head and neck malignancy, accounts for 4% of global cancer cases. The most common type, oral squamous cell carcinoma (OSCC), has a survival rate of about 50%. Even though emerging molecular therapies show promise for managing oral cancer, current treatments like surgery, radiotherapy, and chemotherapy have significant side effects. In addition, the complex tumor microenvironment (TME), involving the extracellular matrix (ECM) and cells like fibroblasts and stromal cells like immune cells, promotes tumor growth and inhibits immune responses, complicating treatment. Nonetheless, immunotherapy is crucial in cancer treatment, especially in oral cancers. Indeed, its effectiveness lies in targeting immune checkpoints such as PD-1 and CTLA-4 inhibitors, as well as monoclonal antibodies like pembrolizumab and cetuximab, adoptive cell transfer methods (including CAR-T cell therapy), cytokine therapy such as IL-2, and tumor vaccines. Thus, these interventions collectively regulate tumor proliferation and metastasis by targeting the TME through autocrine-paracrine signaling pathways. Immunotherapy indeed aims to stimulate the immune system, leveraging both innate and adaptive immunity to counteract cancer cell signals and promote tumor destruction. This review will explore how the TME controls tumor proliferation and metastasis via autocrine-paracrine signaling pathways. It will then detail the effectiveness of immunotherapy in oral cancers, focusing on immune checkpoints, targeted monoclonal antibodies, adoptive cell transfer, cytokine therapy, and tumor vaccines. Graphical abstract Immunotherapy holds a critical position in cancer treatment, particularly in oral cancers. Its effectiveness revolves around immune checkpoints like PD-1 and CTLA-4 inhibitors, targeted monoclonal antibodies such as pembrolizumab and cetuximab, adoptive cell transfer (including CAR-T cell therapy), cytokine therapy like interleukin-2, and tumor vaccines. These interventions collectively target the tumor microenvironment (TME), regulating tumor proliferation and metastasis through autocrine-paracrine signaling pathways.

A growing body of research indicates that a wide range of cancer types may correlate with human microbiome components. On the other hand, little is known about the potential contribution of the oral microbiota to oral cancer. However, some oral microbiome components can stimulate different tumorigenic processes associated with the development of cancer. In this line, two prevalent oral infections, Porphyromonas gingivalis, and Fusobacterium nucleatum can increase tumor growth. The microbiome can impact the course of the illness through direct interactions with the human body and major modifications to the toxicity and responsiveness to different kinds of cancer therapy. Recent research has demonstrated a relationship between specific phylogenetic groupings and the results of immunotherapy treatment for particular tumor types. Conversely, there has been a recent upsurge in interest in the possibility of using microbes to treat cancer. At the moment, some species, such as Salmonella typhimurium and Clostridium spp., are being explored as possible cancer treatment vectors. Thus, understanding these microbial interactions highlights the importance of maintaining a healthy oral microbiome in preventing oral cancers. From this perspective, this review will discuss the role of the microbiome on oral cancers and their possible application in oral cancer treatment/improvement.

A crucial cellular mechanism that has a complex impact on the biology of cancer, particularly in solid tumors, is autophagy. This review explores how metabolic processes trigger autophagy, which helps metastatic tumor cells go dormant and recur. During metastasis, tumor cells frequently encounter severe stressors, such as low oxygen levels and nutritional deprivation, which causes them to activate autophagy as a survival tactic. This process allows cancer stem cells (CSCs) to withstand severe conditions while also preserving their features. After years of dormancy, dormant disseminated tumor cells (DTCs) may reappear as aggressive metastatic cancers. The capacity of autophagy to promote resistance to treatments and avoid immune detection is intimately related to this phenomenon. According to recent research, autophagy promotes processes, such as the epithelial-to-mesenchymal transition (EMT) and helps build a pre-metastatic niche, which makes treatment strategies more challenging. Autophagy may be a promising therapeutic target because of its dual function as a tumor suppressor in early-stage cancer and a survival promoter in advanced stages. To effectively treat metastatic diseases, it is crucial to comprehend how metabolic processes interact with autophagy and affect tumor behavior. In order to find novel therapeutic approaches that can interfere with these processes and improve patient outcomes, this study highlights the critical need for additional investigation into the mechanisms by which autophagy controls tumor dormancy and recurrence.

Centromeres are critical structures involved in chromosome segregation, maintaining genomic stability, and facilitating the accurate transmission of genetic information. They are key in coordinating the assembly and help keep the correct structure, location, and function of the kinetochore, a proteinaceous structure vital for ensuring proper chromosome segregation during cell division. Abnormalities in centromere structure can lead to aneuploidy or chromosomal instability, which have been implicated in various diseases, including cancer. Accordingly, abnormalities in centromeres, such as structural rearrangements and dysregulation of centromere-associated proteins, disrupt gene function, leading to uncontrolled cell growth and tumor progression. For instance, altered expression of CENP-A, CENP-E, and others such as BUB1, BUBR1, MAD1, and INCENP, have been shown to ascribe to centromere over-amplification, chromosome missegregation, aneuploidy, and chromosomal instability; this, in turn, can culminate in tumor progression. These centromere abnormalities also promoted tumor heterogeneity by generating genetically diverse cell populations within tumors. Advanced techniques like fluorescence in situ hybridization (FISH) and chromosomal microarray analysis are crucial for detecting centromere abnormalities, enabling accurate cancer classification and tailored treatment strategies. Researchers are exploring strategies to disrupt centromere-associated proteins for targeted cancer therapies. Thus, this review explores centromere abnormalities in cancer, their molecular mechanisms, diagnostic implications, and therapeutic targeting. It aims to advance our understanding of centromeres’ role in cancer and develop advanced diagnostic tools and targeted therapies for improved cancer management and treatment. Graphical abstract Numerical and structural chromosomal instability are genetic alterations that can lead to cancer development. Numerical instability results from abnormal chromosome numbers, while structural instability involves alterations in chromosome structure, disrupting gene function and forming fusion genes. These alterations can lead to genomic instability, promoting uncontrolled cell growth and cancers.

Cancer is a complex disease driven by multiple genetic changes, including mutations in oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cancer metabolism. Synthetic lethality (SL) is a promising approach in cancer research and treatment, where the simultaneous dysfunction of specific genes or pathways causes cell death. By targeting vulnerabilities created by these dysfunctions, SL therapies selectively kill cancer cells while sparing normal cells. SL therapies, such as PARP inhibitors, WEE1 inhibitors, ATR and ATM inhibitors, and DNA-PK inhibitors, offer a distinct approach to cancer treatment compared to conventional targeted therapies. Instead of directly inhibiting specific molecules or pathways, SL therapies exploit genetic or molecular vulnerabilities in cancer cells to induce selective cell death, offering benefits such as targeted therapy, enhanced treatment efficacy, and minimized harm to healthy tissues. SL therapies can be personalized based on each patient’s unique genetic profile and combined with other treatment modalities to potentially achieve synergistic effects. They also broaden the effectiveness of treatment across different cancer types, potentially overcoming drug resistance and improving patient outcomes. This review offers an overview of the current understanding of SL mechanisms, advancements, and challenges, as well as the preclinical and clinical development of SL. It also discusses new directions and opportunities for utilizing SL in targeted therapy for anticancer treatment.

Resveratrol (RV—3, 5, 4′‐trihydroxystilbene) is a natural compound found in plants like red grapes, berries, and peanuts, with promising effects on dental health. It helps strengthen tooth enamel by promoting remineralization, making the teeth more resistant to decay caused by acid-producing bacteria. RV also shields dentin, a vulnerable layer beneath the enamel, from erosion and sensitivity. Its anti-inflammatory properties can reduce inflammation associated with dental conditions such as pulpitis and endodontic diseases. Moreover, RV’s antimicrobial activity inhibits the growth of bacteria involved in dental plaque and biofilm formation, preventing their accumulation on the tooth surface. This contributes to a healthier oral environment and prolongs the lifespan of dental restorative materials. However, the research on RV’s impact on dental health is in its early stages, and further studies are needed to confirm potential benefits. Important factors such as determining the optimal dosage, understanding its bioavailability, and assessing potential side effects require further investigation. This review focuses on the important role of RV in promoting dental health. It delves into various aspects, including its impact on root health, maintenance of the dental pulp, care for tooth enamel, effectiveness of dental restorative materials, and health of dentin. Graphical abstract The effects of resveratrol on dental health.

Oral cancers, specifically oral squamous cell carcinoma (OSCC), pose a significant global health challenge, with high incidence and mortality rates. Conventional treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness and can result in adverse reactions. However, as an alternative, photodynamic therapy (PDT) has emerged as a promising option for treating oral cancers. PDT involves using photosensitizing agents in conjunction with specific light to target and destroy cancer cells selectively. The photosensitizers accumulate in the cancer cells and generate reactive oxygen species (ROS) upon exposure to the activating light, leading to cellular damage and ultimately cell death. PDT offers several advantages, including its non-invasive nature, absence of known long-term side effects when administered correctly, and cost-effectiveness. It can be employed as a primary treatment for early-stage oral cancers or in combination with other therapies for more advanced cases. Nonetheless, it is important to note that PDT is most effective for superficial or localized cancers and may not be suitable for larger or deeply infiltrating tumors. Light sensitivity and temporary side effects may occur but can be managed with appropriate care. Ongoing research endeavors aim to expand the applications of PDT and develop novel photosensitizers to further enhance its efficacy in oral cancer treatment. This review aims to evaluate the effectiveness of PDT in treating oral cancers by analyzing a combination of preclinical and clinical studies. Graphical Abstract