Circulating autoantibodies against tumor-associated autoantigens (TAA) may serve as valuable biomarkers for a wide range of diagnostic purposes. Modern immunology offers a large variety of methods for in-depth comparative analysis of the repertoires of circulating antibodies’ antigenic specificities in health and disease. Nevertheless, this research field so far has met somewhat limited clinical success, while numerous data on the repertoires of circulating autoantibodies’ specificities in cancer patients are poorly integrated into the contemporary picture of the immunological and molecular landscapes of human tumors. This review is an attempt to identify and systematize the key and essentially universal conceptual and methodological limitations of analyses of the repertoires of circulating antibodies’ antigenic specificities in cancer (expression bias, redundancy of TAA repertoires, identification of natural IgG, the absence of the pathogenetically relevant context in the experimental systems used to detect TAA), as well as to discuss potential and already known methodological improvements that may significantly increase the detectability of the pathogenetically relevant and diagnostically significant bona fide TAA.

The M2 isoform of the glycolytic enzyme pyruvate kinase PKM (PKM2) is at a central focus of current research on cancer metabolism. It functions as a highly adaptive metabolic master regulator, orchestrating a switch between modes of (1) energy generation via highly efficient conversion of phosphoenolpyruvate (PEP) to pyruvate yielding ATP, and (2) accumulation of glycolytic intermediates, which are funneled into various biosynthetic pathways (i.e., biosynthesis of amino acids, nucleotides, and fatty acids). Characterized by exceptional functional and regulatory plasticity, PKM2 represents an ideal tool for metabolic adaptation in the PKM2-expressing cells, particularly in malignant tumors exhibiting severely abnormal metabolic demands. Molecular fingerprints of the PKM2-dependent metabolic adaptation, including PKM2 overexpression, shift of the PKM2 tetramer-dimer equilibrium toward the latter, release of the PKM2 dimer into circulation, and spontaneous tumor-associated immune responses against PKM2, may serve as biomarkers in a wide spectrum of human malignancies. This review provides a comprehensive analysis of the potential of PKM2-dependent metabolic fingerprinting in the diagnosis of human malignancies in the context of the fundamental aspects of PKM2 biology and historical and modern notions on the PKM2-driven metabolic adaptation.