Current Insights into the Role of Peripheral Blood Immune Cell Phenotypes in Resistance to Cancer Therapies.

Abstract

Peripheral blood mononuclear cell (PBMC) immunophenotyping has emerged as a promising non-invasive approach to characterize systemic immune alterations in cancer and to identify biomarkers associated with treatment response and resistance. However, current evidence remains fragmented and predominantly descriptive, with substantial heterogeneity in study design, immunophenotyping methodologies, and patient populations, limiting the identification of robust and clinically translatable immune signatures. In this review, we aim to comprehensively analyze PBMC immune phenotypes across multiple cancer types, with particular emphasis on their association with disease progression, therapeutic outcomes, and the key methodological and translational challenges that currently limit their clinical implementation. Across malignancies, conserved immune features are consistently observed, including T cell exhaustion, regulatory T cell (Treg) expansion, and upregulation of immune checkpoint molecules, reflecting chronic immune activation and dysfunction. In parallel, tumor-specific phenotype, such as peripheral helper T (Tph) cell expansion in non-small cell lung cancer, Vδ1⁺CD69⁺ γδ T cells in hepatocellular carcinoma, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) positive dysfunctional T cells in oral squamous cell carcinoma, highlight the influence of tumor-specific immune contexts. Importantly, this review moves beyond descriptive reporting by integrating mechanistic insights into how PBMC phenotypes contribute to therapeutic resistance. Key mechanisms include immunosuppressive cytokine signaling (e.g., interleukin-10 (IL-10), transforming growth factor-β (TGF-β)), chronic antigen stimulation driving T cell dysfunction, and systemic immune-tumor crosstalk mediated by chemokine axes such as stromal cell-derived factor 1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4). In addition to lymphoid populations, we emphasize the contribution of myeloid cell subsets, including monocytes and myeloid-derived suppressor cells, as central regulators of immune evasion and treatment failure. Despite these advances, significant challenges remain, including the lack of standardized protocols, limited longitudinal and multicenter validation studies, and insufficient integration of multi-omics approaches. Addressing these limitations will be essential for clinical translation. Overall, this review provides a refined conceptual framework that distinguishes conserved and tumor-specific immune signatures and highlights their mechanistic relevance in therapeutic resistance, supporting the development of PBMC immunophenotyping as a tool for personalized cancer immunotherapy.