*2.2. Opportunities for Targeting Immune System with SPION Nanoparticles* 2.2.1. Rational for Targeting Immune System with SPION Nanoparticles

As previously mentioned, in spite of breakthrough advances due to immunotherapy for cancer treatment, there is an urgent need to overcome some major limitations. Several reasons can be mentioned to explain some issues related to these treatments [31]. First, there is an intrinsic variability between patients' immune systems, especially in a context in which they may be immunocompromised by treatments (radiotherapy, chemotherapy), leading to low response rates. Then, as with any cancer therapy, resistance development is inevitable and can be classified as extrinsic (i.e., related to the patient's gender, TME, gut microbiota) or intrinsic resistance due to the nature of the tumor itself (i.e., "cold" versus "hot" tumors). Finally, safety concerns have been frequently reported through immune-related adverse events (irAEs). Indeed, boosting the innate and/or adaptive immune system has a unique set of inflammatory side effects, which can be life-threatening. In this context, nanomedicines designed to enhance antitumor immunity in a variety of ways might represent an interesting alternative, combining efficacy and safety, alone or in combination with other anticancer strategies [38]. Even if anticancer nanomedicines may enhance tumor targeting, the therapeutic responses cannot be guaranteed, especially when they are used in monotherapy. Indeed, we can observe relapse resulting from the re-establishment of pro-tumorigenic conditions (e.g., progenitor immune cells, re-activation of cancer stem cells) [27]. This underlines the need to develop more holistic approaches, notably based on the immune system, taking into account growth-promoting phenomena that occur inside and outside of tumor tissue. So, according to their design, nanomedicines could take advantage of their numerous properties (e.g., targeting moieties, drug payloads, intrinsic properties such as magnetism) to specifically target the immune system while being able to evade clearance from the bloodstream and reticuloendothelial system (RES). Taken together, these data emphasize the interest in using nanomedicines alone or in

combination to target, engage, and modulate immune cells in the TME, circulation, and immune cell-enriched tissues [27].
