Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

Cancer stem cells (CSCs) are broadly considered immature, multipotent, tumorigenic cells within the tumor mass, endowed with the ability to self-renew and escape immune control. All these features contribute to place CSCs at the pinnacle of tumor aggressiveness and (immune) therapy resistance. The immune privileged status of CSCs is induced and preserved by various mechanisms that directly affect them (e.g., the downregulation of the major histocompatibility complex class I) and indirectly are induced in the host immune cells (e.g., activation of immune suppressive cells). Therefore, deeper insights into the immuno-biology of CSCs are essential in our pursuit to find new therapeutic opportunities that eradicate cancer (stem) cells. Here, we review and discuss the ability of CSCs to evade the innate and adaptive immune system, as we offer a view of the immunotherapeutic strategies adopted to potentiate and address specific subsets of (engineered) immune cells against CSCs.

Cancer immunotherapy is the great breakthrough in cancer treatment as it displayed prolonged progression-free survival over conventional therapies, yet, to date, in only a minority of patients. In order to broad cancer immunotherapy clinical applicability some roadblocks need to be overcome, first among all the lack of preclinical models that faithfully depict the local tumor microenvironment (TME), which is known to dramatically affect disease onset, progression and response to therapy. In this review, we provide the reader with a detailed overview of current 3D models developed to mimick the complexity and the dynamics of the TME, with a focus on understanding why the TME is a major target in anticancer therapy. We highlight the advantages and translational potentials of tumor spheroids, organoids and immune Tumor-on-a-Chip models in disease modeling and therapeutic response, while outlining pending challenges and limitations. Thinking forward, we focus on the possibility to integrate the know-hows of micro-engineers, cancer immunologists, pharmaceutical researchers and bioinformaticians to meet the needs of cancer researchers and clinicians interested in using these platforms with high fidelity for patient-tailored disease modeling and drug discovery.