Translational Health Reports

Abstract Background: Colorectal cancer (CRC) remains a major global health issue, with advanced stages difficult to treat. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have improved cancer care, but they work well only in a small group of CRC patients with high microsatellite instability (MSI-H). Most CRC cases are microsatellite stable (MSS) and do not respond to ICI treatment alone, highlighting the need for combined therapies.
Methods: This review summarizes recent studies from PubMed, Google Scholar, and clinical trial databases up to 2025 focusing on why CRC resists ICI treatment. It examines ways to modify the immunosuppressive tumor microenvironment (TME), including using immune-boosting agents and targeting proteins like USP2 that regulate PD-L1.
Results: The immunosuppressive TME in MSS-CRC limits the effectiveness of PD-1 blockers. Immune adjuvants, such as the peptide NCL-P2, can reshape the TME by activating immune cells, increasing T cell entry into tumors, and reducing T cell exhaustion. Additionally, recent studies show that USP2 helps stabilize PD-L1 in cancer cells. Blocking USP2 leads to PD-L1 breakdown, improving T cell attack and boosting anti-PD-1 therapy in lab studies.
Conclusion: Combining anti-PD-1 antibodies with treatments that alter the immunosuppressive TME—such as immune adjuvants to strengthen immune responses and USP2 inhibitors to lower PD-L1 levels—offers a promising multi-target strategy. This method could help overcome treatment resistance and extend immunotherapy benefits to more CRC patients.

Abstract Background: The established first-line treatment for newly diagnosed Glioblastoma Multiforme (GBM) involves maximal surgical removal of the tumor, followed by a regimen of radiotherapy (RT) together with concurrent and maintenance temozolomide (TMZ) chemotherapy. Patient response to this combined approach varies widely and is closely associated with the tumor's molecular characteristics.
Objective: This analysis compiles current research on how the RT/TMZ combination modifies crucial GBM biomarkers over time, focusing on therapy-induced alterations rather than their initial prognostic significance.
Methods: A systematic review of literature from January 2000 to July 2024 was performed using PubMed, Scopus, and Web of Science. Search keywords included "glioblastoma," "radiotherapy," "temozolomide," "MGMT," "IDH," "biomarker," and related terms. Emphasis was placed on clinical trials and key preclinical studies.
Results: The RT/TMZ protocol imposes significant selective pressure, dynamically influencing GBM biomarkers. MGMT promoter methylation is the primary predictor of TMZ efficacy, but treatment often leads to the expansion of MGMT-active, resistant tumor clones at recurrence. IDH1/2 mutations are strong prognostic indicators, and their associated metabolic changes may increase tumor sensitivity to DNA-damaging therapies. Treatment substantially reshapes the tumor immune microenvironment; RT can stimulate anti-tumor immune responses but also increase PD-L1 expression, while TMZ often causes severe lymphocyte depletion. Additionally, therapy promotes the selection of cells with enhanced DNA damage repair mechanisms and activates survival pathways such as EGFR, fostering treatment resistance.
Conclusion: RT and TMZ induce continuous, adaptive changes in GBM biomarkers. Recognizing this dynamic process is essential for personalizing treatment, assessing response, and developing new combination therapies to combat resistance.