Cale is set to undergo surgery after dislocating his shoulder while training with the Wallabies in Perth ahead of Sunday's clash with world champions South Africa.
Western Force star Nick Champion de Crespigny has been rushed into the squad as a replacement.
Cale has a history of shoulder setbacks, missing almost two months of action earlier this year after injuring himself during the Brumbies' Super Rugby win over the Highlanders.
The 194cm powerhouse bravely fought through a shoulder injury for most of 2024, later describing it as like a "ticking time bomb" before undergoing surgery.
Stress fractures in his back derailed a big chunk of Cale's 2025 campaign, and his mettle will now be further tested following his second shoulder setback of 2026.
Cale has been restricted to just six Tests since making his international debut in 2024, but his four Tests under Les Kiss this year proved he's well and truly in the plans for the 2027 home World Cup - if he can get his body fit.
"It was something at a breakdown there, just a recurrence from I think one of the injuries that he had during Super Rugby," Wallabies assistant coach Tom Donnelly said on Tuesday.
"He's still a young man, he's still got a massive future ahead of him.
"A little bit of silver lining is that if it needs to be repaired, he can get it fixed and he can hit the ground running for Super Rugby next year, and give himself a great run into being available for the World Cup."
South Africa arrive in Perth bursting with confidence following their 3-1 series win over fellow powerhouse New Zealand.
The Springboks have rested veteran duo Pieter-Steph du Toit and Damian de Allende for the one-off Test at Optus Stadium, but the two-time defending World Cup champions will still pack a punch, especially at the scrum.
"It's tough. They've been doing it for a few years now, and they've won the World Cup twice," Wallabies prop Taniela Tupou said about taking on South Africa's big forwards.
"We all know they're the best in the world around set piece, around scrum.
"This week it's a good challenge for us to to test ourselves and see where we are as a group."
Springboks coach Rassie Erasmus has already declared his side aren't going to finish off their tour "casually", especially against a Wallabies outfit looking to claim their biggest scalp under Kiss.
The world No.7 Wallabies have posted three wins and a draw under Kiss, but will start as big underdogs against world No.1 South Africa.
Jordan Petaia has been called into the 34-man Wallabies squad for what marks his first return to the national set-up since the 2023 World Cup.
Petaia's dream to forge an NFL career was brought to a swift end last year due to a hamstring injury, but he regained full fitness during a stint in France and is now looking to cement a spot in the Wallabies gold ahead of next year's World Cup.
Western Force recruit Harry McLaughlin-Phillips could make his international debut after being called up to replace fellow flyhalf Carter Gordon (fractured fibula).
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