For MSS/TP53-mutated CRC specifically, we propose an iterative, biology-driven approach: (i) confirm MSS/MMR status and quantify TMB using harmonized panels; (ii) profile TP53 genotype class and clonality together with co-drivers (e.g., KRAS, BRAF, WNT/MAPK components); (iii) assess TME state via transcriptomic/spatial surrogates (interferon signaling, CD8 density, myeloid/TGF-β signatures); and (iv) integrate on-treatment ctDNA kinetics to refine the likelihood of durable benefit. Here, KRAS is linked to colorectal carcinoma.