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Achieving the synergistic optimization among drug-loading capacity, targeting efficacy, and therapeutic potential persists as a critical challenge in the design and development of aptamer-drug conjugate (ApDC). Herein, an innovatively engineered tetra-armed trisubstituted benzene trimer-based linker incorporated multivalent moderately potent chemotherapeutic camptothecin (CPT) and site-specifically conjugated with the aptamer AS1411 to yield the tumor-microenvironment-responsive conjugate AS-CPT-4, self-assembling into well-defined nanoparticles (AS-CPT-4 NPs). The AS-CPT-4 NPs, endowing with dual active-passive targeting capabilities, manifested concurrent enhancement of tumor-specific accumulation and systemic safety profiles. Mechanistically, AS-CPT-4 NPs concurrently induced Topoisomerase I-mediated DNA lesion formation while abrogating CPT-induced NF-κB activation via AS1411-modulated IkK pathway inhibition. Interestingly, AS1411 was initially discovered in conjugates to reprogram the immunosuppressive tumor niche by augmenting CD8⁺ T cell infiltration while concomitantly depleting CD4⁺ T cell populations. In a colon carcinoma mouse model, AS-CPT-4 NPs abrogated off-target toxicity completely and achieved a potent 81.8 % tumor suppression rate, over double the efficacy of the clinically administered hydroxycamptothecin. This research achieved multifaceted enhancement of drug-loading capacity, targeting precision, and therapeutic outcomes through site-specific conjugation technology, thereby establishing a pioneering paradigm for expanding the therapeutic scope of moderately potent cytotoxic agents and overcoming the dual impediments of chemoresistance and immunosuppression.