Fig 2: FAM‐MACTIDE targets CD206+ TAM using different administration routes. Thirty nmol of FAM‐MACTIDE or FAM‐mUNO were administered i.v. (A), i.p. (B), or orally (C) and left to circulate for 24 h. After 24 h, mice were sacrificed, and the organs were collected, fixed, cryoprotected, sectioned, and immunostained for FAM (shown in green) and CD206 (shown in red). The CD206/FAM colocalization indices were calculated from representative images from n = 3 tumors, using Fiji (Mandler's tM2 index) and the signal intensity per CD206+ TAM (i.p. administration) was quantified using ImageJ (B). Scale bars = 100 µm. * p ≤ 0.05, ** p ≤ 0.01 (Anova one‐way fisher LSD).

Fig 3: Design and molecular dynamics of MACTIDE. A) MACTIDE structure with the CD206‐binding motif mUNO in red. B) RMSD to the average structure for heavy atoms of mUNO (red lines) and MACTIDE (green line), in two 400 ns molecular dynamics for mUNO and MACTIDE in solution. C) The two most populated conformations of MACTIDE, C0, and C1, with the mUNO motif in red. D) RMSF of each residue for MACTIDE in solution. E) Intra hydrogen bonds in MACTIDE (dashed blue lines), between Pro7‐Cys10 with an occupancy of 75% and between Ile6‐Thr3 with an occupancy of 10% (present in the C1 conformation); the yellow line indicates the disulfide bond.

Fig 4: MACTIDE‐V promotes a YAP‐ mediated anti‐ tumoral switch in bone marrow‐derived macrophages. Day 5 BMDM were incubated for 4 h with 10 µm conjugates, washed, and followed‐up in media. A) YAP Immunofluorescence (shown in red) was analyzed 3 h after treatment and B) phagocytosis of fluorescent E. coli particles at 48 h follow‐up. C) Flow cytometry on BMDM 48 h after treatment. Left panel, GeoMean of MHC II, CD206, CD80, and PD‐L1 in Balb/c BMDM. Median ± interquartile range. Repeated measures one‐way ANOVA with multiple comparisons, for n = 4 independent experiments. * p ≤ 0.05, ** p ≤ 0.01. D) Heatmap of the mRNA expression of genes involved in the functional activation of BMDM, YAP signaling, and adhesion, measured by real‐time PCR 48 h after treatment in BALB/c BMDM. n = 3 independent experiments.

Fig 5: Docking shows high binding energy of MACTIDE to CD206 and ligand‐induced conformational change. A) CTLD2 domain for cluster node 2 (green) compared with cluster node 0 (purple). MACTIDE is represented as VDW golden spheres. A large alpha helix displacement of 3.8 Å was found in node 2 making space for the peptide to bind. B) Node 2 compared to the crystal structure 5XTS and colored by RMSD. Significant differences (in red) were found in the CysR domain. C) Hydrogen bonds (dashed blue and red lines) formed at the docking pose, where MACTIDE is shown in yellow and CD206 in cyan.