International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 224-234 http://medscipublisher.com/index.php/ijmms 2 31 compared with elderly patients, non-smoking patients, or patients with EGFR mutations, patients under 65 years old, with a smoking history, with EGFR wild-type tumors, or with KRAS mutations gained more survival benefits from immunotherapy (Chen et al., 2024). Whether there are other factors such as brain metastasis or liver metastasis cannot stably predict the therapeutic effect, and there is usually no significant difference in therapeutic effect among patient groups of different genders, histological types and physical conditions. Classification of patients based on these clinical characteristics helps to better select patients suitable for treatment and guide the formulation of personalized treatment plans, especially when the data of molecular biomarkers are uncertain or unavailable (Huo et al., 2022). 7.3 Immune microenvironment and inflammation-related factors The tumor immune microenvironment (TME) plays an important role in influencing the efficacy of PD-1/PD-L1 inhibitors. Massive infiltration of CD8+ T cells in tumors, elevated expression of immune-related genes, and the "inflammatory" state of the TME are all associated with better immunotherapy effects. Conversely, tumors with fewer immune cells or an "immune desert" type (such as non-small cell lung cancer with EGFR mutations or ALK rearrangements) usually have a weaker response to immunotherapy. Furthermore, the presence of inflammatory factors such as the Pulmonary immune prognostic index (LIPI), as well as immune cells such as memory T cells and dendritic cells, can further enhance the predictive ability for therapeutic effects (Chen et al., 2024). Combining TME characteristics with molecular and clinical indicators can provide a more comprehensive approach for predicting the efficacy of chemotherapy combined with immunotherapy in patients with non-small cell lung cancer (Jin et al., 2020). 8 Challenges and Future Prospects Although significant progress has been made in the combination of PD-1/PD-L1 inhibitors and chemotherapy, a major problem still exists - some patients develop drug resistance in the early stage of treatment or after a period of time. Only a small number of NSCLC patients can maintain their therapeutic effect for a long time. The causes of drug resistance include the characteristics of the tumor itself, such as decreased antigen presentation ability, upregulation of other immune checkpoints, and mutations in signaling pathways, and may also be related to external factors such as the inhibition of immune responses by the tumor microenvironment. To address this issue, research focuses on identifying biomarkers that can predict therapeutic efficacy and formulating re-treatment strategies, such as combining immunotherapy with targeted drugs or restarting immunotherapy after drug withdrawal, especially for patients with treatable mutations or those who are initially effective but later relapse. In the future, the treatment of non-small cell lung cancer will develop towards a multi-combination approach that goes beyond traditional chemotherapy and PD-1/PD-L1 inhibition. Currently, multiple clinical trials are evaluating the combined application of immunotherapy with other approaches (such as anti-CTLA-4 antibodies), targeted therapy, radiotherapy, and even traditional Chinese medicine, aiming to enhance the anti-tumor effect and overcome drug resistance. The combination of two immune checkpoint inhibitors (such as PD-1/PD-L1 inhibitors and CTLA-4 blockers), as well as the addition of new drugs like SHP-2 inhibitors and CHK1 inhibitors, has demonstrated potential in preclinical and early clinical studies, providing new treatment ideas for patients who have not responded to existing treatments. Precision immunotherapy is a new treatment model, aiming to formulate a personalized treatment plan based on the biological characteristics of the patient's tumor, the immune microenvironment and their own conditions. The development of high-throughput sequencing, multi-omics analysis and computational models enables us to identify new biomarkers and develop corresponding diagnostic methods, thereby better selecting patients who are most likely to benefit from immunotherapy. Personalized treatment plans may combine molecular characteristics (such as PD-L1 expression, TMB, driver mutations), immune characteristics and clinical features to optimize treatment options, reduce toxic reactions, improve survival benefits, and ultimately provide non-small cell lung cancer patients with more individualized and effective treatment methods. Acknowledgments The author extends sincere thanks to MedSci Publisher for his feedback on the manuscript.
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