It is increasingly apparent that optimal cancer therapies will necessitate combined treatments targeting diverse pathways while minimizing adverse effects. The fusion of nanotechnology with photochemistry presents a unique avenue for delivering and activating multiple drugs concurrently, addressing various regions of cancer cells—including the plasma membrane, cytoplasm, and nucleus. PIC-NAL-IRI stands out as a promising approach to overcome the selectivity-uptake trade-off, enhance the efficacy of photoimmunotherapy, and facilitate multi-tiered cancer targeting. Its ability for controlled drug compartmentalization, facile surface modification, and high clinical relevance collectively underscore the significant value of PIC-NAL-IRI for treatment of primary and metastatic cancer.