Globally, cervical cancer continues to be a highly common form of cancer affecting women(27). With the absolute number of cases taken into account, cervical cancer poses a substantial public health challenge. In cases of recurrent or metastatic cervical cancer where curative intent surgery or radiotherapy is not an option, the standard treatment comprises platinum-based chemotherapy. Clinical data has shown that this approach yields a median overall survival (OS) of approximately 17.5–18.3 months(28). After failure of platinum-based chemotherapeutic regimens in advanced or recurrent situations, patients often exhibit a poor response to other cytotoxic agents(28). In fact, only around 3% of patients usually show responses, and the median period of progression-free survival is approximately 10 months(29). Research indicates that the clinical indicators alone are insufficient for accurately predicting the prognosis of cervical cancer(30). There has been significant advancement in the treatment of cervical cancer through immunotherapy. Platinum-based chemotherapy combined with immunotherapy significantly improves progression-free survival in the KEYNOTE-826 study(31). Now, we require markers capable of predicting the effectiveness of cervical cancer ICI treatment(32). This emphasizes the pressing need for a robust model or target that can accurately assess the overall prognosis of cervical cancer patients and their potential response to immunotherapy.
Disulfidptosis, recently discovered as a regulated form of cell death, emerges as a potential target for metabolic cancer therapies(6, 7, 33). Preclinical studies indicated that metabolic therapy utilizing Glucose Transporter (GLUT) inhibitors can induce Disulfidptosis, subsequently curtailing cancer growth. In preclinical models, the administration of glucose inhibitors initiated Disulfidptosis in cancer cells that overexpress SLC7A11. This intervention effectively impeded tumor growth without inflicting significant harm to healthy tissues(6). The GSEA examination indicated a notable increase in glycolytic pathways within the high-risk category, implying the possibility of tumor management through the use of GLUT inhibitors, which could enhance Disulfidptosis to govern tumor growth and enhance prognosis.
Utilizing the TCGA-CESC dataset, we embarked on the first-ever exploration into the connection between Disulfidptosis-associated long non-coding lncRNAs and the prognosis of CC patients. For the development of a prognosis prediction signature in cervical cancer, we discovered six lncRNAs associated with Disulfidptosis: USP30-AS1, LINC01089, SOX21-AS1, MKLN1-AS, TMEM92-AS1, and DNM3OS. USP30-AS1's role in cervical cancer presents an intriguing conundrum. One study suggested that USP30-AS1 intensified the disease's malignant progression by capturing microRNA-299-3p, consequently leading to PTP4A1 overexpression(34). In contrast, our research proposed that USP30-AS1 functioned as a safeguarding factor in the outlook of cervical cancer. This was further corroborated by our CGCI-HTMCP-CC cohort, which linked USP30-AS1 with substantial immune activation. Furthermore, the inhibition of miR-27a-3p and the upregulation of BTG2 by LINC01089 were discovered to impede the progression of cervical cancer, which is consistent with our prognostic direction(35) Furthermore, the clinical prognostic significance of hypomethylation in SOX21-AS1 was observed in cervical cancer(36). CC patients may view SOX21-AS1 as a hopeful therapeutic target and a possible biomarker(37). Nevertheless, the functions of MKLN1-AS, TMEM92-AS1, and DNM3OS in cervical cancer remain uncertain and necessitate additional research. While their involvement in CC remains uncertain, it is conceivable that they could serve as new indicators linked to CC.
In our study, we observed a marked improvement in the effectiveness of immunotherapy among those in the low-risk category compared to their high-risk counterparts. Furthermore, we discovered elevated expression of numerous immune checkpoint-related genes in the low-risk category This resulted in better immunotherapy responsiveness in the low-risk category, a finding corroborated by Immune Phenotype Score (IPS) data from the TCIA database. In line with previous studies that identified a strong correlation between TLS and elevated PD-1 levels in cervical cancer(38), we discovered that TLS scores were higher in the low-risk category. Moreover, even after stratification between high and low scores, the prognosis remained more favorable for the group with higher TLS scores.
CD8 + T cells, integral components of tumor-infiltrating lymphocytes, are critical in the immunotherapeutic approach to cervical cancer. According to a research, the outlook of cervical cancer is linked to CD8 + T lymphocytes, particularly those influenced by the immune checkpoint-related IDO1 gene(39). A potential beneficial effect on the prognosis of cervical cancer was suggested by the presence of CD8 + T cells, indicating a positive association with IDO1 expression(39). Furthermore, additional studies indicated that inhibiting certain signaling pathways and enhancing the viability and performance of CD8 + T cells could lead to improved antitumor immunity in cervical cancer(40). The observed increase in CD8 + T cells in the low-risk category further confirms their essential function and possible usefulness in immune-focused treatment approaches.
As for drug sensitivity, the GSEA results were consistent in identifying a greater number of oncogenic pathways in the high-scoring group. Consequently, this group exhibited better prognostic responses to various common chemotherapeutic agents including paclitaxel, 5-fluorouracil, methotrexate, camptothecin, cetuximab, rapamycin, and sunitinib. Paclitaxel and 5-fluorouracil are first- and second-line chemotherapy regimens recommended by NCCN guideline, respectively(41).
To summarize, our findings suggest that developing a predictive model with six lncRNAs associated with Disulfidptosis could aid in evaluating the effectiveness of immunotherapy and chemotherapy in treating patients with cervical cancer. The capability of this model to offer valuable observations on patient response assists in optimizing treatment strategies. Nevertheless, it is crucial to recognize the constraints of our research, including the requirement for additional empirical verification and the indispensability of broader multi-center investigations to strengthen the reliability and applicability of the model in forecasting treatment results.