Analysis of tissue biopsy remains the gold-standard method for cancer diagnosis and for selecting biomarker-guided therapies. However, repeated tumour biopsy is invasive and rarely feasible for monitoring dynamic immune responses over time. Advances in technology have enabled multimodal analysis of cells and cellular products in peripheral blood, creating liquid biopsy-based strategies that are minimally invasive and can be repeated across the disease course. These blood-based approaches cannot replace spatial tumour tissue analysis because they do not provide locoregional information on the tumour immune microenvironment, but they offer unique opportunities to monitor systemic immune dynamics, anticipate responses to immunotherapy and detect emerging resistance before clinical progression. The Review discussed here focuses on insights that can be obtained from tumour-derived biomarkers in peripheral blood and from circulating immune cells.
The Review identifies several blood biomarker classes that can inform on tumour burden, immune activation and immune-evasion mechanisms: circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), extracellular vesicles, plasma proteins, platelets and immune cells. Each class provides distinct — and sometimes complementary — types of information. For example, molecular features detected in ctDNA can reflect tumour-derived genomic alterations and burden, whereas CTCs supply information on cellular phenotypes. Extracellular vesicles and plasma proteins may both mediate and indicate immune states, and circulating immune-cell profiles and molecular signatures can reflect systemic immune activity that correlates with intratumoural processes.
ctDNA and CTCs are highlighted as complementary sources of tumour-derived information in blood. ctDNA analyses can report on tumour burden and tumour-specific genomic alterations and are widely studied for applications such as minimal residual disease detection and monitoring response to therapy. CTCs, by contrast, permit interrogation of intact tumour cells and their phenotypes, which can be informative about cellular mechanisms of immune evasion or sensitivity.
The Review notes that clinical interpretation of ctDNA and CTC data is complicated by biological variability in tumour shedding into the circulation and by technical limitations in detection and assay standardization. Tumour-informed and tumour-agnostic assay strategies are compared in the literature, and the analytical validity of ctDNA sequencing assays has been evaluated across studies; however, differences in assay sensitivity, specificity and implementation can affect clinical performance and comparability.
Extracellular vesicles and plasma proteins actively influence and reflect systemic immunity. As functional mediators, extracellular vesicles can carry molecular cargo that modulates immune responses; as biomarkers, their content may indicate immune activation or suppression. Plasma proteins — measured across time points — can likewise serve as markers of immune status or tumour-driven systemic changes. Platelets are also noted among blood components with potential biomarker value. The Review cautions, however, that the specificity and biological complexity of extracellular vesicles and plasma proteins pose challenges for their clinical application as reliable predictive or prognostic markers for immunotherapy.
Circulating immune-cell profiles and molecular signatures derived from blood can reflect aspects of the tumour immune microenvironment. Such signatures may capture systemic immune activation, exhaustion, or other functional states relevant to therapy response. Nevertheless, these circulating signatures do not fully capture spatial or tissue-resident immune contexts, underscoring that blood-based immune profiling is complementary to tissue-based spatial analyses rather than a substitute. The Review emphasizes the potential value of longitudinal immune-cell monitoring to map systemic dynamics during treatment.
A core advantage of liquid biopsy approaches is the ability to obtain repeated measurements over time, enabling longitudinal monitoring of tumour–immune system interactions. This capability offers opportunities to anticipate responses to immunotherapy, detect minimal residual disease and identify the emergence of resistance before overt clinical progression. Blood-based measures therefore have potential utility in precision immuno-oncology as adjuncts to tissue analysis, guiding therapy adjustments and early intervention when resistance mechanisms emerge.
The Review explicitly addresses limitations of blood-based approaches. Primary concerns include the lack of spatial context for intratumoural immune architecture, dilution of tumour-derived material in the circulation, variability in tumour shedding, and technical heterogeneity across assays. These factors complicate the translation of blood biomarker signals into clinical decisions and require careful consideration when interpreting longitudinal changes.
Major barriers to routine clinical implementation are identified: the need for rigorous clinical validation, assay standardization and broad accessibility, plus evidence of cost-effectiveness. The Review also highlights the importance of integrating multi-omic data and artificial intelligence–based analytical approaches to build reliable, interpretable decision-support tools. Such integration must be accompanied by validation and standardization to ensure reproducible, clinically actionable outputs.
The source includes two figures that summarize concepts: one illustrating opportunities and challenges presented by liquid biopsy-based analyses for precision immuno-oncology, and a second depicting the dynamic evolution from immunosurveillance to immune evasion as revealed by blood-based biomarkers. These visual summaries support the Review’s framing of liquid biopsy as a complementary, longitudinal approach to monitoring systemic antitumour immunity.
Liquid biopsy approaches offer minimally invasive, repeatable means to assess systemic antitumour immunity through multiple blood-derived biomarker classes. They complement, but do not replace, tumour tissue analyses, providing information on tumour burden, immune activation and emerging resistance. Widespread clinical use depends on overcoming biological and technical variability, advancing validation and standardization, and creating integrated multi-omic and AI-enabled tools that deliver interpretable, cost-effective decision support.