Apoptosis inhibitor of macrophage (AIM/CD5L) as a potential immunomodulator in feline injection-site sarcoma: a hypothesis on tumor–macrophage interactions

AIM (apoptosis inhibitor of macrophage), also known as CD5L, is a macrophage-derived scavenger protein with broad immunomodulatory roles in mammals. Secreted by tissue macrophages, AIM circulates bound to IgM pentamers, which stabilize the protein in blood; free AIM is released during inflammation to influence immune signaling and cellular homeostasis. (Yang et al. 2023). In cats, AIM exhibits distinctive structural and biochemical properties, existing as both a three-domain (37 kDa) and a four-domain (45 kDa) variant generated through exon 3 duplication (Evangelista et al. 2025), and binding IgM approximately 1000-fold more tightly than murine AIM due to a species-specific positively charged cluster in its third SRCR domain (Miyazaki et al., 2018). These differences suggest feline AIM may function distinctly from human/mouse AIM. Feline injection-site sarcomas (FISS) arise in the context of chronic inflammation and frequently contain abundant tumor-associated macrophages (TAMs)associated with tumor aggressiveness and progression (Gomes et al., 2025). Given AIM's macrophage origin and its established roles in inflammatory regulation, autophagy signaling, and complement-mediated tumor targeting, we propose a directional hypothesis: that the high-affinity IgM-binding of feline AIM constrains free AIM availability in vivo, shifting the functional balance away from complement-mediated tumor cytotoxicity and toward macrophage-intrinsic M2-polarizing pathways, thereby promoting an immunosuppressive tumor microenvironment that contributes to FISS progression. Exploring AIM in this context may provide new perspectives for investigation in feline tumor immunology.