Despite the continuing development of new and more efficient treatments, cancer remains the second cause of premature death worldwide. Multi-faceted interdisciplinary research efforts in industry and academia on different aspects of cancer have provided a knowledge basis for the development of novel therapeutic approaches. Paul Ehrlich, Nobel laureate in Physiology of 1908, had the early vision that a compound could be made to selectively target a disease-causing organism or tumor. A toxin for the particular tissue could be delivered by an agent of selectivity. Such an ideal therapeutic agent would be a "magic bullet" that only kills the target cells. This ETN initiative with the title Magicbullet::reloaded refers to Ehrlich’s bold idea and builds on the previous experience of the highly successful ETN MAGICBULLET (2015-2018, grant agreement No. 642004). As a consequence of the outstanding results, the ETN Magicbullet::reloaded will expand the field of investigation from peptide-drug conjugates (PDCs) to small molecule-drug conjugates (SMDCs) with a special focus on drugs capable to stimulate tumor immune responses and overcome resistance to immuno-therapy. The consortium has been substantially expanded to perfectly address the needs of the new research direction. The planned ETN will design and synthesize an array of SMDCs (including PDCs), also targeting less investigated tumor antigens, investigate their pharmacokinetic behaviour, their implication on the immune system, as well as their tumor selectivity and antitumor activity. The consortium brings together interdisciplinary expert knowledge in Organic Chemistry, Peptide Chemistry, Medicinal Chemistry, Drug Discovery, Biochemistry, Pharmacology and Cell Biology. This high complementarity is required for the different scientific tasks in the development pipeline. Vice versa, the recruited ESRs will be exposed to a challenging research environment leading to a broad range of scientific competences to be acquired.