In the neoadjuvant setting of melanoma treatment, combination therapy of ipilimumab to nivolumab resulted in severe irAEs reaching up to 90% [6]. would be more common and so irAEs. irAEs can present at any time and usually develop within the first few weeks to months of treatment initiation. In the neoadjuvant setting of melanoma treatment, combination therapy of ipilimumab to nivolumab resulted in severe irAEs reaching up to 90% [6]. From a more generalized perspective, irAEs occur in nearly 70% and 50% of those treated with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, respectively, due to the manipulation of the immune system to be more sensitive to these mimicked-receptors that bear high resemblance to innate ones, simultaneously unbalancing the regulatory mechanisms of self-tolerance [7],[8]. As there are still no standardized diagnostic criteria for irAEs, Ptgs1 and considering the heterogeneous genetics, epigenetics, and/or microbiota environment existing from patient to patient, the actual prevalence of irAEs in clinical practice may be under-reported [9]. Despite being associated with greater risk of irAEs and that being one of the reasons why till present monotherapy with anti-CTLA-4 have failed in multiple phase III clinical trials, except in melanoma, anti-CTLA-4 antibody NF 279 was among the first T-cell targeting antibodies to be approved for clinical cancer immunotherapy. Further, treatments offered with anti-CTLA-4 antibodies (Abs) have longer-lasting immunity-effects in cancer patients as compared to anti-PD-1 Abs. However, the underlying mechanisms for these anti-CTLA-4 irAEs remain unclear and thus, in-depth research to improve the efficacy and safety of anti-CTLA-4 Abs are in dire need. To shed the light on this topic, in a recent publication entitled Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy, Zhang et al. [10] investigated the molecular basis for irAEs and cancer immunotherapeutic effects (CITE) of anti-CTLA-4 antibodies. Common practice in immunotherapy is usually using anti-CTLA-4 Abs to inactivate CTLA-4 on T cells, which prevents it to compete with CD28 to interact with the B7 co-stimulatory ligand on APCs, thereby allowing persistent T cell activation NF 279 to target cancer cells. However, it is known that this genetic inactivation of CTLA-4 in mice NF 279 and humans causes severe autoimmune disease [11]. Also, the authors previously reported that blocking the NF 279 conversation between CTLA-4 and B7 is usually neither necessary nor sufficient for CITE of anti-CTLA-4 antibodies [12]. As such, the focus should be placed on selective activation of regulatory T cells in the TME rather than in the generalized tissues for improving the mechanism of action of CITE. Based on these, the authors hypothesized that an antibody-mediated disruption in CTLA-4 recycling might be related to the anti-CTLA-4-induced irAEs. To test this concept, the authors showed that two non-irAEs antibodies failed to downregulate CTLA-4 while two irAEs antibodies (ipilimumab and TremeIgG1) were able to do so as, first, the irAEs-prone Abs were targeted to lysosomes after endocytosis, rather than allowing CTLA-4- lipopolysaccharide-responsive and beige-like anchor (LRBA) interactions for cell surface presentation [2], second, inhibiting the recycling of CTLA-4 molecules in the irAEs-prone Ab-treated cells did not increase the amount of CTLA-4 around the cell surface, and third, the downregulation of CTLA-4 by ipilimumab was inhibited not by a proteasome inhibitor but by a lysosomal degradation inhibitor. Further, the authors also showed that different pH sensitivity anti-CTLA-4 Abs affected differently the CTLA-4 recycling and irAEs in humanized mouse model; simulating that of human irAEs. Hence, the new approach to increase the treatment efficacy of anti-CTLA-4 treatment, without jeopardizing safety, would be to engineer pH sensitivity into anti-CTLA-4 Abs. For validate this notion, the authors evinced several impactful findings. First, their data exhibited that.