Coronavirus disease-2019 COVID-19 exhibits marked inter-individual variability in susceptibility and clinical outcomes, suggesting a role for host genetic factors. Vitamin D exerts immunomodulatory effects through the vitamin D receptor (VDR), and genetic variation in the VDR gene may influence host responses to SARS-CoV-2 infection. This study aimed to investigate the association between VDR-gene polymorphisms—FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232), and BsmI (rs1544410)—and COVID-19 susceptibility in the Kurdish population. The FokI polymorphism was significantly associated with COVID-19 susceptibility. Interestingly, the GG-genotype was more frequent among Patients than controls and was associated with increased odds of infection (OR = 9.00; 95% CI: 3.22–25.15; p < 0.0001), whereas the AG-genotype was associated with reduced susceptibility (OR = 0.33; 95% CI: 0.14–0.76; p = 0.001). Additionally, the G-allele was also more prevalent in Patients than controls (OR = 1.87; 95% CI: 1.21–2.89; p = 0.004). Similarly, the TaqI TT-genotype was more frequent among Patients and was associated with increased susceptibility (OR = 36.0; 95% CI: 11.2–115.8; p < 0.0001). In contrast, the ApaI AA-genotype was less frequent among Patients and was associated with reduced odds of COVID-19 susceptibility under a recessive model (OR = 0.15; 95% CI: 0.03–0.68; p = 0.003). Moreover, the BsmI polymorphism was monomorphic in both groups and therefore not informative. Genetic variation in the VDR gene, particularly at the FokI, TaqI, and ApaI loci, was associated with COVID-19 susceptibility in the case–control study, while BsmI showed no variations. These findings suggest that genetic variation in the VDR gene may contribute to inter-individual differences in susceptibility to SARS-CoV-2 infection in the Kurdish population. Larger studies incorporating functional validation and detailed clinical data are required to confirm these associations.

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies.

Inflammatory joint diseases, including osteoarthritis, are multifactorial disorders in which dysregulated innate immune signaling and non-coding RNA (ncRNA)-mediated regulation of gene expression play essential roles. MicroRNA-155 (miR-155), its host gene MIR155HG, and Toll-like receptor 4 (TLR4) form a tightly linked inflammatory signaling axis, yet their combined genetic variability in chronic joint inflammation remains insufficiently characterized. The aim of this study was to investigate genetic variants in MIR155HG exon 3, mature miR-155, and TLR4 exon 3 and assess their potential synergistic role in chronic inflammatory joint disease. A case–control study was conducted with 100 cases (50 osteoarthritis patients and 50 matched healthy controls). Genomic DNA was analysed using polymerase chain reaction (PCR) and Sanger sequencing. Variant alleles and genotypes were identified, and their allele frequencies and genotypes were calculated using Mutation Surveyor. Detected variants were compared with public databases, and in silico tools were used to estimate the structural impact of TLR4 missense mutations. Sixteen heterozygous variants were identified in MIR155HG exon 3, most of them novel and population-specific. Interestingly, the highest variant frequencies for MIR155HG exon 3 were observed at positions 12448G>GC and 12481T>TA (both 64.3%), followed by 12442T>TC (57.1%). Additionally, two novel variants were detected in the miR-155 gene (chr21:29,694,314 G>A and chr21:29,646,351 T>C), each present at an allele frequency of 7.1% and absent from current external variant databases. Moreover, two rare TLR4 exon-3 variants were identified; a synonymous variant, c.147C>A (Pro49Pro; rs375037549), and a missense mutation, c.148G>A (Asp50Asn; rs776561489). Notably, in silico analyses and molecular dynamic simulations indicated that the Asp50Asn (D50N) substitution destabilizes the TLR4 protein. Conclusion: Concurrent variants in MIR155HG, miR-155, and TLR4 suggest a convergent regulatory molecular axis that may contribute to disease susceptibility and inflammatory progression.