Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), present significant challenges owing to their complex pathologies and a lack of curative treatments. Early detection and reliable biomarkers are critical but remain elusive. Artificial intelligence (AI) has emerged as a transformative tool, enabling advancements in biomarker discovery, diagnostic accuracy, and therapeutic development. From optimizing clinical-trial designs to leveraging omics and neuroimaging data, AI facilitates understanding of disease and treatment innovation. Notably, technologies such as AlphaFold and deep learning models have revolutionized proteomics and neuroimaging, offering unprecedented insights into ALS pathophysiology. This review highlights the intersection of AI and ALS, exploring the current state of progress and future therapeutic prospects.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by the progressive degeneration of motor neurons, resulting in muscle weakness, paralysis, and, ultimately, death. Presently, no effective treatment for ALS has been established. Although motor neuron dysfunction is a hallmark of ALS, emerging evidence suggests that sensory neurons are also involved in the disease. In clinical research, 30% of patients with ALS had sensory symptoms and abnormal sensory nerve conduction studies in the lower extremities. Peroneal nerve biopsies show histological abnormalities in 90% of the patients. Preclinical research has reported several genetic abnormalities in the sensory neurons of animal models of ALS, as well as in motor neurons. Furthermore, the aggregation of misfolded proteins like TAR DNA-binding protein 43 has been reported in sensory neurons. This review aims to provide a comprehensive description of ALS-related sensory neuron dysfunction, focusing on its clinical changes and underlying mechanisms. Sensory neuron abnormalities in ALS are not limited to somatosensory issues; proprioceptive sensory neurons, such as MesV and DRG neurons, have been reported to form networks with motor neurons and may be involved in motor control. Despite receiving limited attention, sensory neuron abnormalities in ALS hold potential for new therapies targeting proprioceptive sensory neurons.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including as first-line, adjuvant, and neoadjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Cervical lymph node metastasis is a major predictor of poor prognosis in patients with oral squamous cell carcinoma (OSCC), underscoring the need for therapies that effectively target metastatic spread. We previously reported that G47Δ, a third‐generation oncolytic herpes simplex virus type 1 (HSV‐1), rapidly traffics from tongue tumors to cervical lymph nodes and suppresses metastasis in murine models. Based on this lymphotropic property and the immunological significance of CD28–B7‐1 interactions for T‐cell activation, we pursue the potential of T‐mB7‐1, a new G47Δ‐derived oncolytic HSV‐1 expressing soluble murine B7‐1. T‐mB7‐1 secreted soluble B7‐1 in vitro without compromising cytopathic activity. In vivo, intratumoral T‐mB7‐1 suppressed tumor growth in the resistant KLN205‐MUC1 subcutaneous model and prolonged survival in SCCVII orthotopic tongue tumors. In the KLN205‐MUC1 orthotopic tongue cancer that exhibits rapid lymphatic metastasis, a single dose of T‐mB7‐1, but not the control virus T‐01, significantly reduced cervical lymph node metastasis and improved survival. Repeated low‐dose T‐mB7‐1 further caused near‐complete suppression of lymph node metastasis and markedly extended survival. Flow cytometry showed both T‐01 and T‐mB7‐1 induced CD69 ⁺ T‐cell activation in cervical lymph nodes at 18 h, which was reduced with T‐mB7‐1 at 24 h. Importantly, combining T‐mB7‐1 with systemic CTLA‐4 blockade markedly prolonged survival of mice harboring orthotopic KLN205‐MUC1 tumors, with all treated mice surviving beyond 80 days in the otherwise fatal model. These findings demonstrate that soluble B7‐1‐expressing oncolytic HSV‐1 combined with CTLA‐4 blockade durably suppresses lymph node metastasis, providing a promising and minimally invasive strategy for regionally metastatic OSCC.