Cancers 2021, 13, 813. https://doi.org/10.3390/cancers13040813 www.mdpi.com/journal/cancers Review Anti-Cancer Auto-Antibodies: Roles, Applications and Open Issues Hugo de Jonge, Luisa Iamele, Maristella Maggi, Greta Pessino and Claudia Scotti * Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; hugo.dejonge@unipv.it (H.d.J.); luisa.iamele@unipv.it (L.I.); maristella.maggi@unipv.it (M.M.); greta.pessino01@universitadipavia.it (G.P.) * Correspondence: claudia.scotti@unipv.it Simple Summary: Cancer is one of the main causes of death worldwide and early detection is cru- cial for effective treatment. Scientists have therefore focused on the identification of circulating can- cer-specific molecules, so-called markers, that can be detected with non- or less-invasive techniques. One attractive emerging marker is represented by circulating antibodies against molecules that are specific for the tumor cells and not produced by normal cells. Many such auto-antibodies have been discovered, but still not much is known about their significance and role in either promoting or inhibiting tumor growth. The aim of this review is to summarize the current knowledge on auto- antibodies in different cancer types and on their current or possible utilization for effective cancer management. Reference to autoimmune diseases will also be made, as they share with cancer the presence of such auto-antibodies. Abstract: Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels. However, recent evidence is accumulating on the presence of auto-antibodies against single or selected panels of auto-antigens in many types of cancer. Auto- antibodies might initially represent an epiphenomenon derived from the inflammatory environ- ment induced by the tumor. However, their effect on tumor evolution can be crucial, as is discussed in this paper. It has been demonstrated that some of these auto-antibodies can be used for early detection and cancer staging, as well as for monitoring of cancer regression during treatment and follow up. Interestingly, certain auto-antibodies were found to promote cancer progression and me- tastasis, while others contribute to the body’s defense against it. Moreover, auto-antibodies are of a polyclonal nature, which means that often several antibodies are involved in the response to a single tumor antigen. Dissection of these antibody specificities is now possible, allowing their identifica- tion at the genetic, structural, and epitope levels. In this review, we report the evidence available on the presence of auto-antibodies in the main cancer types and discuss some of the open issues that still need to be addressed by the research community. Keywords: auto-antibodies; cancer; tumor-associated antigens; tumor-specific antigens 1. Introduction Cancer is one of the leading causes of death worldwide along with cardiovascular diseases. Huge progress has been made during the last few decades towards early detec- tion, effective treatment, and follow-up, giving oncologists powerful tools in the fight against cancer. However, more research is needed to reduce mortality and increase qual- ity of life and disease-free survival for patients. In this perspective, the search for new markers as indicators for the presence of tumors and as tools to monitor disease progres- sion is essential. Moreover, the discovery of each new marker opens the possibility to shed light on potentially new pathophysiological mechanisms. This is particularly true when antibodies are considered, because of the central role they have in the immune response. Citation: De Jonge, H.; Iamele, L.; Maggi, M.; Pessino, G.; Scotti, C., Anti-cancer auto-antibodies: roles, applications and open issues. Cancers 2021, 13, 813. https:// doi.org/10.3390/cancers13040813 Academic editor: Theodoros Rampias Received: 6 January 2021 Accepted: 10 February 2021 Published: 15 February 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and insti- tutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (http://cre- ativecommons.org/licenses/by/4.0/).