Thoeris defense systems protect bacteria from infection by phages via abortive infection. In these systems, ThsB proteins serve as sensors of infection and generate signaling nucleotides that activate ThsA effectors. Silent information regulator and SMF/DprA-LOG (SIR2-SLOG) containing ThsA effectors are activated by cyclic ADP-ribose (ADPR) isomers 2′cADPR and 3′cADPR, triggering abortive infection via nicotinamide adenine dinucleotide (NAD+) depletion. Here, we characterize Thoeris systems with transmembrane and macro domain (TM-macro)–containing ThsA effectors. We demonstrate that ThsA macro domains bind ADPR and imidazole adenine dinucleotide (IAD), but not 2′cADPR or 3′cADPR. Combining crystallography, in silico predictions, and site-directed mutagenesis, we show that ThsA macro domains form nucleotide-induced higher-order oligomers, enabling TM domain clustering. We demonstrate that ThsB can produce both ADPR and IAD, and we identify a ThsA TM-macro–specific ThsB subfamily with an active site resembling deoxy-nucleotide and deoxy-nucleoside processing enzymes. Collectively, our study demonstrates that Thoeris systems with SIR2-SLOG and TM-macro ThsA effectors trigger abortive infection via distinct mechanisms.