Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 245 Although significant progress has been made in predictive biomarkers for CRC immunotherapy, many challenges remain, including standardized testing of biomarkers, integration and analysis of multi-omics data, and how to effectively translate basic research results into clinical applications. This requires more in-depth research in the future. By leveraging these biomarkers, clinicians can better stratify patients, personalize treatment plans, and improve outcomes in colon cancer immunotherapy. 7 Challenges and Future Directions 7.1 Overcoming immune resistance One of the significant challenges in modulating the immune microenvironment for colon cancer therapy is overcoming immune resistance. Tumors employ various mechanisms to evade immune detection and destruction, including the upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of inhibitory cytokines. For instance, the immunosuppressive tumor microenvironment, characterized by high levels of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), significantly hampers the effectiveness of immunotherapies (Bao et al., 2020; Scolaro et al., 2024). Interestingly, recent developments in single-cell sequencing have advanced the study of reprogramming the immune microenvironment(Huang et al., 2024a). Strategies such as combination therapies using immune checkpoint inhibitors and agents that target these immunosuppressive cells are under investigation to overcome this resistance (Shi et al., 2019). 7.2 Enhancing immune memory Another crucial direction for future research is enhancing immune memory to ensure long-term protection against cancer recurrence. Current immunotherapies often fail to induce robust and durable immune memory, which is essential for preventing tumor relapse. Enhancing the generation and persistence of memory T cells through vaccination strategies and adjuvants, as well as optimizing the timing and sequencing of immunotherapies, could significantly improve outcomes (Huang et al., 2024b; Jia et al., 2024; Song et al., 2024). Recent studies suggest that combining immunotherapies with agents that promote the survival and function of memory T cells may provide lasting anti-tumor immunity (Yu and Cui, 2018). Memory-like (ML) NK cells differentiated overcome many challenges to effective NK cell anti-tumor responses (Marin et al., 2024). 7.3 Personalized immunotherapy approaches Personalized immunotherapy approaches tailored to the unique genetic and immunological landscape of each patient's tumor are crucial for improving therapeutic efficacy. Advances in genomic and transcriptomic technologies have enabled the identification of specific mutations, neoantigens, and immune signatures that can be targeted for personalized treatment. Integrating multi-omics data can help identify biomarkers for predicting response to therapy and guide the development of individualized treatment plans. For example, the use of tumor mutational burden (TMB) and microsatellite instability (MSI) as biomarkers has shown promise in selecting patients for immune checkpoint inhibitor therapy (Lazarus et al., 2018; Wang et al., 2020b). Currently, suitable biomarkers that can guide immunotherapy efficacy are still in continuous exploration (Li et al., 2024). 7.4 Integrating multi-omics data for better understanding The integration of multi-omics data, including genomics, transcriptomics, proteomics, and metabolomics, offers a comprehensive understanding of the tumor microenvironment and its interaction with the immune system. This holistic approach can uncover novel therapeutic targets and pathways involved in immune evasion and resistance. For instance, analyzing the molecular nature associated with microsatellite status in colon cancer can provide insights into the mechanisms of immune escape and identify potential targets for therapy (Bao et al., 2020). Microbiota-metabolite-immune crosstalk might also explain tumor resistance to immunotherapy. The gut microbiota, for example, F. nucleatum-derived succinic acid suppressed the cGAS-interferon- β pathway, limiting CD8 T cell and consequently inhibiting antitumor response (Jiang et al., 2023). However, current studies on microbiota are highly heterogeneous, which still needs more researches (Cheng et al., 2024; Derosa et al., 2024). Furthermore, the development of advanced computational models and bioinformatics tools is essential for integrating and interpreting these complex datasets, ultimately leading to the design of more effective and personalized immunotherapies (Visalakshan et al., 2023).
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