The 20th century began with chemotherapy’s blunt assault on cells, effective  yet destructive. The 1975 discovery of monoclonal antibodies introduced precision-guided " biological missiles ", culminating in Herceptin’s 1997 debut as the first targeted therapy against HER2. The 21st century breakthrough of antibody-drug conjugates (ADCs) elevated this precision: antibodies now act as smart delivery systems, directing cytotoxic payloads into tumors. From indiscriminate bombardment to precision strikes, this century-spanning revolution embodies Sun Tzu ’ s timeless.

Figure 1 Paul Ehrlich (1854-1915) Chapter2     Here Disitamab Vedotin Comes

Disitamab Vedotin (RC48) is an innovative antibody-drug conjugate (ADC) composed of three key components: a novel monoclonal antibody (disitamab) that binds with high affinity to different epitopes of HER2 on tumor cells; a stable linker that connects the antibody to the cytotoxic payload; and monomethyl auristatin E (MMAE), a potent microtubule-binding agent.

Figure 2 The structure of RC48

Upon binding to HER2 on the tumor cell surface, the ADC-HER2 complex is internalized via endocytosis. Within the cell, the linker connecting the antibody and MMAE is cleaved by lysosomal proteases, releasing MMAE into the cytoplasm. MMAE then binds to microtubules, inhibiting their polymerization and triggering programmed cell death in the tumor cells.

Figure 3 The mechanism of RC48 Chapter3     The "Roadblock"

“There is no fixed formation in warfare, just as there is no fixed shapein water.”

—— Sun Tzu

Despite RC48's revolutionary targeting of HER2-positive bladder cancer, resistance remains a significant challenge, as is the case with many antibody-drug conjugates. Like water adapting to terrain, cancer cells evolve stealth tactics to evade treatment. How do we outmaneuver an enemy that rewrites its playbook daily?

Figure 4 Can Hou Yi shoot down the stronger sun? Chapter4     Evolve to Counter Evolve

“Know thy enemy and know yourself; in a hundred battles, never peril.”

—— Sun Tzu

Resistance is no accident but an arms race. To conquer, we must map the enemy’s playbook.
To know the enemy, we became the enemy. Through iterative RC48 exposure (40 → 500 μg/mL over 20 weeks), we forged T24-RC48 — a mirror of clinical resistance. Its 10-fold IC₅₀ surge (P<0.001) echoes.

        Figure 5    Drug susceptibility test results diagram

When the enemy digs trenches, we map every foxhole. Multi-omics intel exposes resistance's Achilles' heel: Integrated proteomic and transcriptomic analyses revealed 120 co-differentially expressed genes. WGS uncovered 3,155,367 SNPs, among which 19,802 were located in exonic regions, 1,718,276 in intergenic regions, and 546 in splicing regions. Among the coding SNPs, an average of 10,017 synonymous and 9,245 missense mutations were detected per sample. Additionally, 923,236 InDels were identified, including 571 in exonic regions, 468,933 in intergenic regions, and 385 in splicing regions. Within the coding InDels, each sample carried on average 68 frameshift deletions, 61 frameshift insertions, 177 non-frameshift deletions, and 149 non-frameshift insertions.”

Figure 6 Overview of multi-omics analysis results Epilogue

"The skillful combatant imposes his will on the enemy, but does not allow the enemy's will to be imposed on him"

—— Sun Tzu

Resistance is not failure—it's evolution. And evolution is the catalyst for innovation. By studying how resistance works, we can use it as a blueprint to design better treatments. By dissecting the intricate mechanisms of resistance, we've turned their armor into a blueprint. The next front? Preemptive strategies that leverage our growing understanding of resistance pathways, transforming vulnerabilities into therapeutic opportunities.