Remodeling the immune microenvironment: Engineering IL-2 variants to overcome clinical bottlenecks in PD-1 inhibitor plus chemotherapy.

The perioperative regimen of chemotherapy plus PD-1 inhibitors in gastric cancer has significantly improved event-free survival (EFS), yet its translation into overall survival (OS) benefits remains frequently inadequate, constituting a core clinical dilemma. This review systematically elucidates the potential reasons for the significant improvement in event-free survival (EFS) but insufficient improvement in overall survival (OS) from the perspective of the immune microenvironment, particularly emphasizing the incomplete remodeling of the immunosuppressive microenvironment, which specifically includes the failure to induce stem cell-like memory T cells capable of conferring long-term protection. In this field, current research is increasingly focused on interleukin-2 (IL-2) variants, with PD-1/IL-2 bispecific antibodies, in particular, representing a significant research hotspot that holds considerable promise for achieving breakthroughs. Through precise synergy with existing regimens, they achieve profound immune reprogramming across three dimensions: expanding tumor-specific T cell clones, reversing T cell exhaustion and driving memory differentiation, and inverting the balance between effector cells and suppressor cells in the. Overall, the emergence of PD-1/IL-2 bispecific antibodies, represents a promising approach in cancer therapy with the potential to enhance long-term survival outcomes for patients.