Lasers based on biological materials are attracting an increasing interest in view of their use in integrated and transient photonics. DNA as optical biopolymer in combination with highly-emissive dyes has been reported to have excellent potential in this respect, however achieving miniaturized lasing systems based on solid-state DNA shaped in different geometries to confine and enhance emission is still a challenge, and physico-chemical mechanisms originating fluorescence enhancement are not fully understood. Herein, a class of wavelength-tunable lasers based on DNA nanofibers is demonstrated, for which optical properties are highly controlled through the system morphology. A synergistic effect is highlighted at the basis of lasing action. Through a quantum chemical investigation, we show that the interaction of DNA with the encapsulated dye leads to hindered twisting and suppressed channels for the non-radiative decay. This is combined with effective waveguiding, optical gain, and tailored mode confinement to promote morphologically-controlled lasing in DNA-based nanofibers. The results establish design rules for the development of bright and tunable nanolasers and optical networks based on DNA nanostructures.